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Calcium Channels and Pumps in Cancer: Changes and Consequences*

Open AccessPublished:July 20, 2012DOI:https://doi.org/10.1074/jbc.R112.343061
      Increases in intracellular free Ca2+ play a major role in many cellular processes. The deregulation of Ca2+ signaling is a feature of a variety of diseases, and modulators of Ca2+ signaling are used to treat conditions as diverse as hypertension to pain. The Ca2+ signal also plays a role in processes important in cancer, such as proliferation and migration. Many studies in cancer have identified alterations in the expression of proteins involved in the movement of Ca2+ across the plasma membrane and subcellular organelles. In some cases, these Ca2+ channels or pumps are potential therapeutic targets for specific cancer subtypes or correlate with prognosis.

      Introduction

      Our understanding of calcium signaling and its intersection with specific processes important in tumor progression is only recent. We now appreciate that altered expression of specific Ca2+ channels and pumps is a characterizing feature of some cancers. By comparison, the link between calcium signaling and other conditions, such as cardiovascular and neurological diseases, was made many years ago. The direct link between Ca2+ and processes linked to a specific pathology, such as vascular tone and neurotoxicity, meant that these conditions attracted the initial focus of researchers devoted to defining the role of Ca2+ in disease.
      In their seminal review “The Hallmarks of Cancer,” Hanahan and Weinberg (
      • Hanahan D.
      • Weinberg R.A.
      The hallmarks of cancer.
      ) described six acquired characteristics of cancers: the ability to evade apoptosis, self-sufficiency in growth signaling, insensitivity to anti-growth signals, the capacity to invade and metastasize, “limitless” replication potential, and the promotion of angiogenesis. Calcium signaling is linked either directly or indirectly to each of these processes, and this has been reviewed elsewhere (
      • Roderick H.L.
      • Cook S.J.
      Ca2+ signaling checkpoints in cancer: remodeling Ca2+ for cancer cell proliferation and survival.
      ,
      • Prevarskaya N.
      • Skryma R.
      • Shuba Y.
      Calcium in tumor metastasis: new roles for known actors.
      ,
      • Fiorio Pla A.
      • Avanzato D.
      • Munaron L.
      • Ambudkar I.S.
      Ion channels and transporters in cancer. 6. Vascularizing the tumor: TRP channels as molecular targets.
      ,
      • Rizzuto R.
      • Pinton P.
      • Ferrari D.
      • Chami M.
      • Szabadkai G.
      • Magalhães P.J.
      • Di Virgilio F.
      • Pozzan T.
      Calcium and apoptosis: facts and hypotheses.
      ,
      • Lehen'kyi V.
      • Shapovalov G.
      • Skryma R.
      • Prevarskaya N.
      Ion channnels and transporters in cancer. 5. Ion channels in control of cancer and cell apoptosis.
      ). A remodeling of calcium homeostasis can occur in cancer cells. Although alterations in Ca2+ signaling may not be a requirement for the initiation of cancer, the consequences of altered calcium transport in cancer cells may be significant and contribute to tumor progression. Characterizing such changes may help to identify new therapeutic targets. In this minireview, we discuss how remodeling of Ca2+ signaling is a feature of some cancers and provide examples of how this remodeling is often achieved through the differential expression of specific Ca2+ pumps and channels. Examples of this remodeling are discussed, particularly those that illustrate the complexities of expression changes and their contribution to tumor progression.

      Ca2+ Transport in Cancer Cells

      Cancer cells use the same calcium channels, pumps, and exchangers as non-malignant cells. However, there are often key alterations in calcium channels and pumps in cancer cells. Such changes in cancer cells may include the expression of calcium channels or pumps (or their specific isoforms) not normally present in non-malignant cells of the same cell type, pronounced changes in the level of expression (as outlined in Table 1), altered cellular localization, altered activity through changes in post-translational modification, gene mutations, and changes in activity or expression associated with specific cancer-relevant processes (e.g. migration). These changes are often reflected in alterations in Ca2+ flux across the plasma membrane or across intracellular organelles.
      TABLE 1Examples of altered expression of calcium channels and pumps in human cancers
      Ca2+ pump or channelCancer typeChange with cancerRef.
      mRNAProtein
      Transient receptor potential channels
      TRPC1Breast cancer: patient tissue samples
      ↑, increase; ↓, decrease; ↔, no significant difference.
      • Dhennin-Duthille I.
      • Gautier M.
      • Faouzi M.
      • Guilbert A.
      • Brevet M.
      • Vaudry D.
      • Ahidouch A.
      • Sevestre H.
      • Ouadid-Ahidouch H.
      High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters.
      TRPC3Ovarian cancer: patient tissue samples
      • Yang S.L.
      • Cao Q.
      • Zhou K.C.
      • Feng Y.J.
      • Wang Y.Z.
      Transient receptor potential channel C3 contributes to the progression of human ovarian cancer.
      Breast cancer: patient tissue samples
      • Aydar E.
      • Yeo S.
      • Djamgoz M.
      • Palmer C.
      Abnormal expression, localization, and interaction of canonical transient receptor potential ion channels in human breast cancer cell lines and tissues: a potential target for breast cancer diagnosis and therapy.
      TRPC6Esophageal cancer: patient tissue samples
      • Shi Y.
      • Ding X.
      • He Z.H.
      • Zhou K.C.
      • Wang Q.
      • Wang Y.Z.
      Critical role of TRPC6 channels in G2 phase transition and the development of human esophageal cancer.
      Glioma: patient tissue samples
      • Ding X.
      • He Z.
      • Zhou K.
      • Cheng J.
      • Yao H.
      • Lu D.
      • Cai R.
      • Jin Y.
      • Dong B.
      • Xu Y.
      • Wang Y.
      Essential role of TRPC6 channels in G2/M phase transition and development of human glioma.
      Liver cancer: patient tissue samples
      • El Boustany C.
      • Bidaux G.
      • Enfissi A.
      • Delcourt P.
      • Prevarskaya N.
      • Capiod T.
      Capacitative calcium entry and transient receptor potential canonical 6 expression control human hepatoma cell proliferation.
      Breast cancer: patient tissue samples
      • Aydar E.
      • Yeo S.
      • Djamgoz M.
      • Palmer C.
      Abnormal expression, localization, and interaction of canonical transient receptor potential ion channels in human breast cancer cell lines and tissues: a potential target for breast cancer diagnosis and therapy.
      ,
      • Dhennin-Duthille I.
      • Gautier M.
      • Faouzi M.
      • Guilbert A.
      • Brevet M.
      • Vaudry D.
      • Ahidouch A.
      • Sevestre H.
      • Ouadid-Ahidouch H.
      High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters.
      TRPM7Pancreatic cancer: patient tissue samples
      • Rybarczyk P.
      • Gautier M.
      • Hague F.
      • Dhennin-Duthille I.
      • Chatelain D.
      • Kerr-Conte J.
      • Pattou F.
      • Regimbeau J.M.
      • Sevestre H.
      • Ouadid-Ahidouch H.
      Transient receptor potential melastatin-related 7 channel is overexpressed in human pancreatic ductal adenocarcinomas and regulates human pancreatic cancer cell migration.
      Breast cancer: patient tissue samples
      • Dhennin-Duthille I.
      • Gautier M.
      • Faouzi M.
      • Guilbert A.
      • Brevet M.
      • Vaudry D.
      • Ahidouch A.
      • Sevestre H.
      • Ouadid-Ahidouch H.
      High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters.
      TRPM8Pancreatic cancer: cell lines (mRNA) and patient tissue samples (protein)
      • Yee N.S.
      • Zhou W.
      • Lee M.
      Transient receptor potential channel TRPM8 is overexpressed and required for cellular proliferation in pancreatic adenocarcinoma.
      Prostate cancer: cell lines and patient tissue samples
      • Tsavaler L.
      • Shapero M.H.
      • Morkowski S.
      • Laus R.
      Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins.
      ,
      • Prevarskaya N.
      • Skryma R.
      • Bidaux G.
      • Flourakis M.
      • Shuba Y.
      Ion channels in death and differentiation of prostate cancer cells.
      ,
      • Schmidt U.
      • Fuessel S.
      • Koch R.
      • Baretton G.B.
      • Lohse A.
      • Tomasetti S.
      • Unversucht S.
      • Froehner M.
      • Wirth M.P.
      • Meye A.
      Quantitative multigene expression profiling of primary prostate cancer.
      Breast cancer: patient tissue samples
      • Tsavaler L.
      • Shapero M.H.
      • Morkowski S.
      • Laus R.
      Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins.
      ,
      • Dhennin-Duthille I.
      • Gautier M.
      • Faouzi M.
      • Guilbert A.
      • Brevet M.
      • Vaudry D.
      • Ahidouch A.
      • Sevestre H.
      • Ouadid-Ahidouch H.
      High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters.
      Melanoma: patient tissue samples
      • Tsavaler L.
      • Shapero M.H.
      • Morkowski S.
      • Laus R.
      Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins.
      Colorectal cancer: patient tissue samples
      • Tsavaler L.
      • Shapero M.H.
      • Morkowski S.
      • Laus R.
      Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins.
      Lung cancer: patient tissue samples
      • Tsavaler L.
      • Shapero M.H.
      • Morkowski S.
      • Laus R.
      Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins.
      TRPV1Bladder cancer: patient tissue samples
      • Kalogris C.
      • Caprodossi S.
      • Amantini C.
      • Lambertucci F.
      • Nabissi M.
      • Morelli M.B.
      • Farfariello V.
      • Filosa A.
      • Emiliozzi M.C.
      • Mammana G.
      • Santoni G.
      Expression of transient receptor potential vanilloid-1 (TRPV1) in urothelial cancers of human bladder: relation to clinicopathological and molecular parameters.
      Prostate cancer: patient tissue samples
      • Czifra G.
      • Varga A.
      • Nyeste K.
      • Marincsák R.
      • Tóth B.I.
      • Kovács I.
      • Kovács L.
      • Bíró T.
      Increased expressions of cannabinoid receptor-1 and transient receptor potential vanilloid-1 in human prostate carcinoma.
      TRPV6Breast cancer: patient tissue samples
      • Fixemer T.
      • Wissenbach U.
      • Flockerzi V.
      • Bonkhoff H.
      Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression.
      ,
      • Bolanz K.A.
      • Hediger M.A.
      • Landowski C.P.
      The role of TRPV6 in breast carcinogenesis.
      ,
      • Dhennin-Duthille I.
      • Gautier M.
      • Faouzi M.
      • Guilbert A.
      • Brevet M.
      • Vaudry D.
      • Ahidouch A.
      • Sevestre H.
      • Ouadid-Ahidouch H.
      High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters.
      ,
      • Zhuang L.
      • Peng J.B.
      • Tou L.
      • Takanaga H.
      • Adam R.M.
      • Hediger M.A.
      • Freeman M.R.
      Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies.
      Prostate cancer: patient tissue samples
      • Fixemer T.
      • Wissenbach U.
      • Flockerzi V.
      • Bonkhoff H.
      Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression.
      ,
      • Zhuang L.
      • Peng J.B.
      • Tou L.
      • Takanaga H.
      • Adam R.M.
      • Hediger M.A.
      • Freeman M.R.
      Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies.
      Thyroid cancer: patient tissue samples
      • Zhuang L.
      • Peng J.B.
      • Tou L.
      • Takanaga H.
      • Adam R.M.
      • Hediger M.A.
      • Freeman M.R.
      Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies.
      Colon cancer: patient tissue samples
      • Zhuang L.
      • Peng J.B.
      • Tou L.
      • Takanaga H.
      • Adam R.M.
      • Hediger M.A.
      • Freeman M.R.
      Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies.
      Ovarian cancer: patient tissue samples
      • Zhuang L.
      • Peng J.B.
      • Tou L.
      • Takanaga H.
      • Adam R.M.
      • Hediger M.A.
      • Freeman M.R.
      Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies.
      Voltage-gated calcium channels
      Cav1.2Colon cancer: patient tissue samples
      • Wang X.T.
      • Nagaba Y.
      • Cross H.S.
      • Wrba F.
      • Zhang L.
      • Guggino S.E.
      The mRNA of L-type calcium channel elevated in colon cancer: protein distribution in normal and cancerous colon.
      Cav3.2Prostate cancer: patient tissue samples
      • Gackière F.
      • Bidaux G.
      • Delcourt P.
      • Van Coppenolle F.
      • Katsogiannou M.
      • Dewailly E.
      • Bavencoffe A.
      • Van Chuoï-Mariot M.T.
      • Mauroy B.
      • Prevarskaya N.
      • Mariot P.
      CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells.
      Store-operated calcium channels
      ORAI1Breast cancer: cell lines
      • McAndrew D.
      • Grice D.M.
      • Peters A.A.
      • Davis F.M.
      • Stewart T.
      • Rice M.
      • Smart C.E.
      • Brown M.A.
      • Kenny P.A.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      ORAI1-mediated calcium influx in lactation and in breast cancer.
      ,
      • Motiani R.K.
      • Abdullaev I.F.
      • Trebak M.
      A novel native store-operated calcium channel encoded by Orai3: selective requirement of Orai3 versus Orai1 in estrogen receptor-positive versus estrogen receptor-negative breast cancer cells.
      ORAI3Breast cancer: cell lines and patient tissue samples (mRNA only)↑, ↔
      • McAndrew D.
      • Grice D.M.
      • Peters A.A.
      • Davis F.M.
      • Stewart T.
      • Rice M.
      • Smart C.E.
      • Brown M.A.
      • Kenny P.A.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      ORAI1-mediated calcium influx in lactation and in breast cancer.
      ,
      • Motiani R.K.
      • Abdullaev I.F.
      • Trebak M.
      A novel native store-operated calcium channel encoded by Orai3: selective requirement of Orai3 versus Orai1 in estrogen receptor-positive versus estrogen receptor-negative breast cancer cells.
      ,
      • Faouzi M.
      • Hague F.
      • Potier M.
      • Ahidouch A.
      • Sevestre H.
      • Ouadid-Ahidouch H.
      Down-regulation of Orai3 arrests cell cycle progression and induces apoptosis in breast cancer cells but not in normal breast epithelial cells.
      Plasma membrane calcium ATPases
      PMCA2Breast cancer: cell lines (mRNA only) and patient tissue samples
      • VanHouten J.
      • Sullivan C.
      • Bazinet C.
      • Ryoo T.
      • Camp R.
      • Rimm D.L.
      • Chung G.
      • Wysolmerski J.
      PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer.
      ,
      • Lee W.J.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      Plasma membrane calcium ATPases 2 and 4 in human breast cancer cell lines.
      PMCA4Colon cancer: patient tissue samples
      • Aung C.S.
      • Ye W.
      • Plowman G.
      • Peters A.A.
      • Monteith G.R.
      • Roberts-Thomson S.J.
      Plasma membrane calcium ATPase 4 and the remodeling of calcium homeostasis in human colon cancer cells.
      Store release channels
      IP3R1Glioblastoma: patient tissue samples
      • Kang S.S.
      • Han K.S.
      • Ku B.M.
      • Lee Y.K.
      • Hong J.
      • Shin H.Y.
      • Almonte A.G.
      • Woo D.H.
      • Brat D.J.
      • Hwang E.M.
      • Yoo S.H.
      • Chung C.K.
      • Park S.H.
      • Paek S.H.
      • Roh E.J.
      • Lee S.J.
      • Park J.Y.
      • Traynelis S.F.
      • Lee C.J.
      Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.
      IP3R3Glioblastoma: patient tissue samples
      • Kang S.S.
      • Han K.S.
      • Ku B.M.
      • Lee Y.K.
      • Hong J.
      • Shin H.Y.
      • Almonte A.G.
      • Woo D.H.
      • Brat D.J.
      • Hwang E.M.
      • Yoo S.H.
      • Chung C.K.
      • Park S.H.
      • Paek S.H.
      • Roh E.J.
      • Lee S.J.
      • Park J.Y.
      • Traynelis S.F.
      • Lee C.J.
      Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.
      Colorectal cancer: patient tissue samples
      • Shibao K.
      • Fiedler M.J.
      • Nagata J.
      • Minagawa N.
      • Hirata K.
      • Nakayama Y.
      • Iwakiri Y.
      • Nathanson M.H.
      • Yamaguchi K.
      The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma.
      Sarcoplasmic/endoplasmic reticulum calcium ATPases
      SERCA2Oral cancer: cell lines (mRNA only) and patient tissue samples
      • Endo Y.
      • Uzawa K.
      • Mochida Y.
      • Shiiba M.
      • Bukawa H.
      • Yokoe H.
      • Tanzawa H.
      Sarco/endoplasmic reticulum Ca2+-ATPase type 2 down-regulated in human oral squamous cell carcinoma.
      SERCA3Colon cancer: cell lines and patient tissue samples
      • Gélébart P.
      • Kovács T.
      • Brouland J.P.
      • van Gorp R.
      • Grossmann J.
      • Rivard N.
      • Panis Y.
      • Martin V.
      • Bredoux R.
      • Enouf J.
      • Papp B.
      Expression of endomembrane calcium pumps in colon and gastric cancer cells. Induction of SERCA3 expression during differentiation.
      Breast cancer: patient tissue samples
      • Papp B.
      • Brouland J.P.
      Altered endoplasmic reticulum calcium pump expression during breast tumorigenesis.
      Secretory pathway calcium ATPases
      SPCA1Breast cancer: basal-like clinical samples and cell lines
      • Grice D.M.
      • Vetter I.
      • Faddy H.M.
      • Kenny P.A.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      Golgi calcium pump secretory pathway calcium ATPase 1 (SPCA1) is a key regulator of insulin-like growth factor receptor (IGF1R) processing in the basal-like breast cancer cell line MDA-MB-231.
      SPCA2Breast cancer: cell lines and patient tissue samples (mRNA only)
      MCF-7 versus MCF-10A.
      • Feng M.
      • Grice D.M.
      • Faddy H.M.
      • Nguyen N.
      • Leitch S.
      • Wang Y.
      • Muend S.
      • Kenny P.A.
      • Sukumar S.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      • Rao R.
      Store-independent activation of Orai1 by SPCA2 in mammary tumors.
      a ↑, increase; ↓, decrease; ↔, no significant difference.
      b MCF-7 versus MCF-10A.

      Ca2+ Influx in Cancer

      The influx of calcium across the plasma membrane into the cell is a key trigger or regulator of cellular processes relevant to tumor progression, including proliferation, migration, and apoptosis. Ca2+-permeable ion channels of almost every class have now been associated with aspects of tumor progression. This minireview will particularly focus on transient receptor potential (TRP)
      The abbreviations used are: TRP
      transient receptor potential
      PMCA
      plasma membrane Ca2+-ATPase
      SERCA
      sarco/endoplasmic reticulum Ca2+-ATPase
      SPCA
      secretory pathway Ca2+-ATPase.
      channels and ORAI-mediated store-operated Ca2+ influx as examples of Ca2+ influx pathways altered in some cancers.

      TRP Channels

      TRP ion channels consist of six subfamilies, with most members permeable to Ca2+, many of which have a role in distinguishing sensations, including pain, temperature, taste, and pressure (
      • Ramsey I.S.
      • Delling M.
      • Clapham D.E.
      An introduction to TRP channels.
      ). This family is arguably the most studied ion channel class in cancer. The key early work on calcium signaling in cancer was focused on cancers of the prostate gland and more specifically the calcium-permeable ion channel TRPM8 (
      • Tsavaler L.
      • Shapero M.H.
      • Morkowski S.
      • Laus R.
      Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins.
      ). Although now studied predominately in the context of its role as a cold receptor (
      • McKemy D.D.
      • Neuhausser W.M.
      • Julius D.
      Identification of a cold receptor reveals a general role for TRP channels in thermosensation.
      ,
      • Knowlton W.M.
      • Daniels R.L.
      • Palkar R.
      • McCoy D.D.
      • McKemy D.D.
      Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice.
      ), TRPM8 was first identified by its overexpression in some prostate cancers (
      • Tsavaler L.
      • Shapero M.H.
      • Morkowski S.
      • Laus R.
      Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins.
      ). Early work by Zhang and Barritt (
      • Zhang L.
      • Barritt G.J.
      Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells.
      ) demonstrated that both the silencing of TRPM8 and menthol-mediated activation of TRPM8 reduced the viability of LNCaP prostate cancer cells. That both activators and inhibitors are proposed as potential therapeutic agents for prostate cancer cells that overexpress TRPM8 is reflective of the duality of the calcium signal (
      • Monteith G.R.
      • McAndrew D.
      • Faddy H.M.
      • Roberts-Thomson S.J.
      Calcium and cancer: targeting Ca2+ transport.
      ), whereby Ca2+ is both a key regulator of proliferation and, in the case of Ca2+ overload, an initiator of cell death. The ability of TRPM8 activation by prostate-specific antigen to inhibit the migration of PC3 prostate cancer cells now extends the applicability of channel activators as therapeutics beyond just inducers of cancer cell death (
      • Gkika D.
      • Flourakis M.
      • Lemonnier L.
      • Prevarskaya N.
      PSA reduces prostate cancer cell motility by stimulating TRPM8 activity and plasma membrane expression.
      ). Further detailed work on TRPM8 in prostate cancer showed androgen-mediated increases in TRPM8 in LNCaP prostate cancer cells (
      • Zhang L.
      • Barritt G.J.
      Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells.
      ,
      • Bidaux G.
      • Roudbaraki M.
      • Merle C.
      • Crépin A.
      • Delcourt P.
      • Slomianny C.
      • Thebault S.
      • Bonnal J.L.
      • Benahmed M.
      • Cabon F.
      • Mauroy B.
      • Prevarskaya N.
      Evidence for specific TRPM8 expression in human prostate secretory epithelial cells: functional androgen receptor requirement.
      ). This finding provides one of the first examples of hormone-mediated changes in the expression of a calcium-permeable ion channel in a cancer cell line. As discussed below, this has now been seen with other calcium channels and pumps in breast cancers.
      The contribution of TRPM8 to cancer progression, as we will see for other Ca2+ channels and pumps, may not always involve its classic role (in this case as a plasmalemmal ion channel). As opposed to the usual plasma membrane localization, endoplasmic reticulum localization of TRPM8 is observed in some prostate cancer cells (
      • Zhang L.
      • Barritt G.J.
      Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells.
      ,
      • Bidaux G.
      • Flourakis M.
      • Thebault S.
      • Zholos A.
      • Beck B.
      • Gkika D.
      • Roudbaraki M.
      • Bonnal J.L.
      • Mauroy B.
      • Shuba Y.
      • Skryma R.
      • Prevarskaya N.
      Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function.
      ), with the consequence being reduced levels of endoplasmic reticulum Ca2+ and increased resistance to apoptosis (
      • Bidaux G.
      • Flourakis M.
      • Thebault S.
      • Zholos A.
      • Beck B.
      • Gkika D.
      • Roudbaraki M.
      • Bonnal J.L.
      • Mauroy B.
      • Shuba Y.
      • Skryma R.
      • Prevarskaya N.
      Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function.
      ). Aside from prostate cancer, overexpression of TRPM8 is also associated with other cancer types, including melanoma and cancers of the pancreas, breast, colon, and lung (see Table 1). However, the utility of TRPM8 as a target for cancer therapy might be limited and require knowledge of the individual tumor expression of the channel. For example, TRPM8 expression actually appears to decrease as prostate cancer cells transition to androgen independence and increased aggressiveness (
      • Henshall S.M.
      • Afar D.E.
      • Hiller J.
      • Horvath L.G.
      • Quinn D.I.
      • Rasiah K.K.
      • Gish K.
      • Willhite D.
      • Kench J.G.
      • Gardiner-Garden M.
      • Stricker P.D.
      • Scher H.I.
      • Grygiel J.J.
      • Agus D.B.
      • Mack D.H.
      • Sutherland R.L.
      Survival analysis of genome-wide gene expression profiles of prostate cancers identifies new prognostic targets of disease relapse.
      ,
      • Prevarskaya N.
      • Skryma R.
      • Bidaux G.
      • Flourakis M.
      • Shuba Y.
      Ion channels in death and differentiation of prostate cancer cells.
      ).
      TRPV6 is another TRP channel linked to prostate cancer. TRPV6 levels correlate with tumor progression and have been proposed as a predictor of invasiveness (
      • Fixemer T.
      • Wissenbach U.
      • Flockerzi V.
      • Bonkhoff H.
      Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression.
      ,
      • Lehen'kyi V.
      • Flourakis M.
      • Skryma R.
      • Prevarskaya N.
      TRPV6 channel controls prostate cancer cell proliferation via Ca2+/NFAT-dependent pathways.
      ). TRPV6 is highly Ca2+-selective and is constitutively active (
      • Wissenbach U.
      • Niemeyer B.A.
      Trpv6.
      ). When TRPV6 expression is silenced in LNCaP prostate cancer cells, there is inhibition of Ca2+ influx and consequently reduced activation of NFAT. Crucially, this illustrates the importance of calcium-dependent transcription pathways as a mechanism for tumor promotion (
      • Lehen'kyi V.
      • Flourakis M.
      • Skryma R.
      • Prevarskaya N.
      TRPV6 channel controls prostate cancer cell proliferation via Ca2+/NFAT-dependent pathways.
      ).
      Like TRPM8, alterations in TRPV6 expression are not confined to cancers of the prostate, with increased expression levels reported in thyroid, colon, ovarian, and breast cancers (see Table 1). In breast cancers, the expression of TRPV6 varies widely between tumors (
      • Bolanz K.A.
      • Hediger M.A.
      • Landowski C.P.
      The role of TRPV6 in breast carcinogenesis.
      ). The consequences of TRPV6 overexpression in tumors may relate to effects on cancer cell survival, as TRPV6 silencing in T47D breast cancer cells reduces cell viability (
      • Bolanz K.A.
      • Hediger M.A.
      • Landowski C.P.
      The role of TRPV6 in breast carcinogenesis.
      ). Further studies are needed to address the mechanisms leading to TRPV6 overexpression in cancers and the association between TRPV6 levels and breast cancer prognosis. Analogous to the androgen dependence of TRPM8 expression in LNCaP prostate cancer cells, TRPV6 levels also appear to be hormonally regulated, with estradiol increasing TRPV6 mRNA in T47D breast cancer cells (
      • Bolanz K.A.
      • Hediger M.A.
      • Landowski C.P.
      The role of TRPV6 in breast carcinogenesis.
      ).
      Other examples of TRP channels that are overexpressed in multiple cancer types include TRPC3 and TRPC6. TRPC3 is elevated in some breast (
      • Aydar E.
      • Yeo S.
      • Djamgoz M.
      • Palmer C.
      Abnormal expression, localization, and interaction of canonical transient receptor potential ion channels in human breast cancer cell lines and tissues: a potential target for breast cancer diagnosis and therapy.
      ) and ovarian epithelial tumors, and its silencing reduces ovarian cancer cell line proliferation in vitro and tumor formation in vivo (
      • Yang S.L.
      • Cao Q.
      • Zhou K.C.
      • Feng Y.J.
      • Wang Y.Z.
      Transient receptor potential channel C3 contributes to the progression of human ovarian cancer.
      ). TRPC6 is elevated in cancers of the breast, liver, stomach, and esophagus and in gliomas (
      • Aydar E.
      • Yeo S.
      • Djamgoz M.
      • Palmer C.
      Abnormal expression, localization, and interaction of canonical transient receptor potential ion channels in human breast cancer cell lines and tissues: a potential target for breast cancer diagnosis and therapy.
      ,
      • Shi Y.
      • Ding X.
      • He Z.H.
      • Zhou K.C.
      • Wang Q.
      • Wang Y.Z.
      Critical role of TRPC6 channels in G2 phase transition and the development of human esophageal cancer.
      ,
      • Ding X.
      • He Z.
      • Zhou K.
      • Cheng J.
      • Yao H.
      • Lu D.
      • Cai R.
      • Jin Y.
      • Dong B.
      • Xu Y.
      • Wang Y.
      Essential role of TRPC6 channels in G2/M phase transition and development of human glioma.
      ), and its silencing reduces the proliferation of some esophageal and breast cancer cell lines and glioma cell lines (
      • Aydar E.
      • Yeo S.
      • Djamgoz M.
      • Palmer C.
      Abnormal expression, localization, and interaction of canonical transient receptor potential ion channels in human breast cancer cell lines and tissues: a potential target for breast cancer diagnosis and therapy.
      ,
      • Shi Y.
      • Ding X.
      • He Z.H.
      • Zhou K.C.
      • Wang Q.
      • Wang Y.Z.
      Critical role of TRPC6 channels in G2 phase transition and the development of human esophageal cancer.
      ,
      • Ding X.
      • He Z.
      • Zhou K.
      • Cheng J.
      • Yao H.
      • Lu D.
      • Cai R.
      • Jin Y.
      • Dong B.
      • Xu Y.
      • Wang Y.
      Essential role of TRPC6 channels in G2/M phase transition and development of human glioma.
      ). For esophageal and glioma cell lines, these effects are due to G2/M cell cycle arrest (
      • Shi Y.
      • Ding X.
      • He Z.H.
      • Zhou K.C.
      • Wang Q.
      • Wang Y.Z.
      Critical role of TRPC6 channels in G2 phase transition and the development of human esophageal cancer.
      ,
      • Ding X.
      • He Z.
      • Zhou K.
      • Cheng J.
      • Yao H.
      • Lu D.
      • Cai R.
      • Jin Y.
      • Dong B.
      • Xu Y.
      • Wang Y.
      Essential role of TRPC6 channels in G2/M phase transition and development of human glioma.
      ).
      The importance of some TRP channels in tumor progression appears to extend beyond the primary tumor. Fiorio Pla et al. (
      • Fiorio Pla A.
      • Ong H.L.
      • Cheng K.T.
      • Brossa A.
      • Bussolati B.
      • Lockwich T.
      • Paria B.
      • Munaron L.
      • Ambudkar I.S.
      TRPV4 mediates tumor-derived endothelial cell migration via arachidonic acid-activated actin remodeling.
      ) showed that migrating endothelial cells have a greater cytosolic calcium response to the TRPV4 activator 4-α-phorbol 12,13-didecanoate than non-migrating cells. Furthermore, they showed increased expression of TRPV4 in endothelial cells derived from breast cancers compared with those derived from normal tissue, implicating TRPV4 as a possible key component in angiogenesis associated with breast cancers. Other Ca2+ channels have also been associated with angiogenesis, as reviewed recently (
      • Fiorio Pla A.
      • Avanzato D.
      • Munaron L.
      • Ambudkar I.S.
      Ion channels and transporters in cancer. 6. Vascularizing the tumor: TRP channels as molecular targets.
      ).
      Calcium entry into the cell via some TRP channels may result in localized Ca2+ signals that contribute to cancer cell migration (
      • Prevarskaya N.
      • Skryma R.
      • Shuba Y.
      Calcium in tumor metastasis: new roles for known actors.
      ). One example of such a localized event is referred to as Ca2+ flickers (
      • Wei C.
      • Wang X.
      • Chen M.
      • Ouyang K.
      • Song L.S.
      • Cheng H.
      Calcium flickers steer cell migration.
      ), which are highly localized (∼5-μm diameter) and transient (10 ms to 4 s) increases in Ca2+ that control the direction of migration as lung fibroblasts move toward a growth factor. Ca2+ flickers during migration are regulated by TRPM7 (
      • Wei C.
      • Wang X.
      • Chen M.
      • Ouyang K.
      • Song L.S.
      • Cheng H.
      Calcium flickers steer cell migration.
      ), which may act as a stretch or mechanical sensing channel (
      • Numata T.
      • Shimizu T.
      • Okada Y.
      TRPM7 is a stretch- and swelling-activated cation channel involved in volume regulation in human epithelial cells.
      ). With TRPM7 inhibition, there is a reduction in migration of a number of cancer cell types, including those of the pancreas, lung, and nasopharynx (
      • Rybarczyk P.
      • Gautier M.
      • Hague F.
      • Dhennin-Duthille I.
      • Chatelain D.
      • Kerr-Conte J.
      • Pattou F.
      • Regimbeau J.M.
      • Sevestre H.
      • Ouadid-Ahidouch H.
      Transient receptor potential melastatin-related 7 channel is overexpressed in human pancreatic ductal adenocarcinomas and regulates human pancreatic cancer cell migration.
      ,
      • Gao H.
      • Chen X.
      • Du X.
      • Guan B.
      • Liu Y.
      • Zhang H.
      EGF enhances the migration of cancer cells by up-regulation of TRPM7.
      ,
      • Chen J.P.
      • Luan Y.
      • You C.X.
      • Chen X.H.
      • Luo R.C.
      • Li R.
      TRPM7 regulates the migration of human nasopharyngeal carcinoma cell by mediating Ca2+ influx.
      ).
      The examples above highlight some studies in which cancer cells have been associated with a remodeling of TRP channel expression or in which TRP channels have been linked to specific processes important in tumor progression. The interest and understanding of TRP channels in cancer are likely to expand in the coming years, and these channels may represent the first class of ion channel targeted for the treatment of a specific cancer.

      Store-operated Ca2+ Influx

      Store-operated Ca2+ entry is a critical Ca2+ influx pathway and represents the major Ca2+ influx mechanism in non-excitable cells (
      • Parekh A.B.
      • Putney Jr., J.W.
      Store-operated calcium channels.
      ), such as those of the epithelia, from where most cancers originate. The pathway involves the activation of Ca2+ influx upon intracellular Ca2+ store depletion (
      • Parekh A.B.
      • Putney Jr., J.W.
      Store-operated calcium channels.
      ,
      • Roberts-Thomson S.J.
      • Peters A.A.
      • Grice D.M.
      • Monteith G.R.
      ORAI-mediated calcium entry: mechanism and roles, diseases and pharmacology.
      ,
      • Hogan P.G.
      • Rao A.
      Dissecting ICRAC, a store-operated calcium current.
      ). The canonical components of store-operated Ca2+ entry are the calcium influx channel ORAI1 and the endoplasmic Ca2+ depletion sensor STIM1 (stromal interaction molecule 1) (
      • Feske S.
      • Gwack Y.
      • Prakriya M.
      • Srikanth S.
      • Puppel S.H.
      • Tanasa B.
      • Hogan P.G.
      • Lewis R.S.
      • Daly M.
      • Rao A.
      A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function.
      ,
      • Roos J.
      • DiGregorio P.J.
      • Yeromin A.V.
      • Ohlsen K.
      • Lioudyno M.
      • Zhang S.
      • Safrina O.
      • Kozak J.A.
      • Wagner S.L.
      • Cahalan M.D.
      • Veliçelebi G.
      • Stauderman K.A.
      STIM1, an essential and conserved component of store-operated Ca2+ channel function.
      ). Although this pathway has rapidly become one of the Ca2+ influx pathways most studied in breast cancer, it also appears to be an important Ca2+ influx route during lactation (
      • McAndrew D.
      • Grice D.M.
      • Peters A.A.
      • Davis F.M.
      • Stewart T.
      • Rice M.
      • Smart C.E.
      • Brown M.A.
      • Kenny P.A.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      ORAI1-mediated calcium influx in lactation and in breast cancer.
      ), suggesting an important role in normal breast function.
      ORAI1 and STIM1 silencing in MDA-MB-231 breast cancer cells reduces migration, invasion through Matrigel, and the establishment of lung metastasis after tail vein injection in NOD/SCID mice (
      • Yang S.
      • Zhang J.J.
      • Huang X.Y.
      Orai1 and STIM1 are critical for breast tumor cell migration and metastasis.
      ), the latter of which can be mimicked by the pharmacological store-operated Ca2+ influx inhibitor SKF96365 (
      • Yang S.
      • Zhang J.J.
      • Huang X.Y.
      Orai1 and STIM1 are critical for breast tumor cell migration and metastasis.
      ). The anti-metastasis effects of ORAI1 and STIM1 silencing appear to be due in part to alterations in focal adhesion turnover (
      • Yang S.
      • Zhang J.J.
      • Huang X.Y.
      Orai1 and STIM1 are critical for breast tumor cell migration and metastasis.
      ). The effects of ORAI1 silencing on breast cancer cells are not restricted to inhibition of processes important in migration; ORAI1 silencing has antiproliferative properties in MCF-7 breast cancer cells in culture and in vivo. These changes may be due in part to reductions in basal Ca2+ influx, leading to reduced ERK1/2 phosphorylation and cyclin D1 expression (
      • Feng M.
      • Grice D.M.
      • Faddy H.M.
      • Nguyen N.
      • Leitch S.
      • Wang Y.
      • Muend S.
      • Kenny P.A.
      • Sukumar S.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      • Rao R.
      Store-independent activation of Orai1 by SPCA2 in mammary tumors.
      ).
      Alterations in the expression of specific components of store-operated Ca2+ entry are also a feature of some breast cancer cells. ORAI1 mRNA levels are higher in some breast cancer cell lines compared with non-malignant breast cell lines (
      • McAndrew D.
      • Grice D.M.
      • Peters A.A.
      • Davis F.M.
      • Stewart T.
      • Rice M.
      • Smart C.E.
      • Brown M.A.
      • Kenny P.A.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      ORAI1-mediated calcium influx in lactation and in breast cancer.
      ). When breast cancer subtypes are stratified by gene expression, basal breast cancers (associated with a poor prognosis and a lack of effective therapies) are characterized by an elevated STIM1/STIM2 ratio. Correspondingly, those patients with breast cancers with a high STIM1/STIM2 ratio and high STIM1 levels have significantly reduced survival (
      • McAndrew D.
      • Grice D.M.
      • Peters A.A.
      • Davis F.M.
      • Stewart T.
      • Rice M.
      • Smart C.E.
      • Brown M.A.
      • Kenny P.A.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      ORAI1-mediated calcium influx in lactation and in breast cancer.
      ), placing STIM proteins as either potential key regulators or biomarkers of breast cancer progression. The significance of STIM1 may extend beyond breast cancers given its role in the migration of cervical cancer cells (
      • Chen Y.F.
      • Chiu W.T.
      • Chen Y.T.
      • Lin P.Y.
      • Huang H.J.
      • Chou C.Y.
      • Chang H.C.
      • Tang M.J.
      • Shen M.R.
      Calcium store sensor stromal interaction molecule 1-dependent signaling plays an important role in cervical cancer growth, migration, and angiogenesis.
      ). The mechanisms responsible for enhanced ORAI1-mediated Ca2+ influx in breast cancer appear to be complex and related to cancer subtypes. As discussed below, in addition to STIM1-mediated activation of ORAI1, some breast cancers that overexpress the SPCA2 isoform may be characterized by elevated ORAI1-mediated Ca2+ influx.
      The ORAI1 isoform is not the only ORAI protein with a cancer association. ORAI3 protein levels and ORAI3-dependent store-operated Ca2+ influx are both elevated in estrogen receptor-positive breast cancer cell lines (
      • Motiani R.K.
      • Abdullaev I.F.
      • Trebak M.
      A novel native store-operated calcium channel encoded by Orai3: selective requirement of Orai3 versus Orai1 in estrogen receptor-positive versus estrogen receptor-negative breast cancer cells.
      ) compared with estrogen receptor-negative cell lines, in which store-operated Ca2+ influx is mediated predominately by ORAI1. A strengthening of the causative link with cancer was provided by a study in estrogen receptor-positive MCF-7 breast cancer cells in which ORAI3 silencing inhibited proliferation through G1 arrest (
      • Faouzi M.
      • Hague F.
      • Potier M.
      • Ahidouch A.
      • Sevestre H.
      • Ouadid-Ahidouch H.
      Down-regulation of Orai3 arrests cell cycle progression and induces apoptosis in breast cancer cells but not in normal breast epithelial cells.
      ). Although the examples above point to an up-regulation of ORAI-mediated influx, some cancer types might be associated with a down-regulation of this pathway that may in turn help in the acquisition of apoptotic resistance (
      • Lehen'kyi V.
      • Shapovalov G.
      • Skryma R.
      • Prevarskaya N.
      Ion channnels and transporters in cancer. 5. Ion channels in control of cancer and cell apoptosis.
      ). Indeed, reduced ORAI1-mediated Ca2+ influx and expression are features of androgen-independent prostate cancer cells, and silencing of ORAI1 reduces apoptosis in LNCaP cells (
      • Flourakis M.
      • Lehen'kyi V.
      • Beck B.
      • Raphaël M.
      • Vandenberghe M.
      • Abeele F.V.
      • Roudbaraki M.
      • Lepage G.
      • Mauroy B.
      • Romanin C.
      • Shuba Y.
      • Skryma R.
      • Prevarskaya N.
      Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.
      ).
      In this minireview, we have given examples of how ORAI1 may regulate processes important for carcinogenesis, including cell proliferation, migration, and apoptosis sensitivity, and this may occur in a store-dependent or store-independent manner. Examples of how ORAI1 regulates these key cancer processes are shown schematically in Fig. 1.
      Figure thumbnail gr1
      FIGURE 1ORAI1 regulates processes important for cancer cell proliferation, migration, and apoptosis. A, in MCF-7 human breast cancer cells, SPCA2 partially localizes to the plasma membrane and interacts with ORAI1 to mediate store-independent Ca2+ influx. This is associated with phosphorylation of ERK1/2, nuclear translocation of NFAT, and increased cell proliferation (
      • Feng M.
      • Grice D.M.
      • Faddy H.M.
      • Nguyen N.
      • Leitch S.
      • Wang Y.
      • Muend S.
      • Kenny P.A.
      • Sukumar S.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      • Rao R.
      Store-independent activation of Orai1 by SPCA2 in mammary tumors.
      ). B, silencing of ORAI1 or STIM1 in MDA-MB-231 human breast cancer cells reduces store-operated Ca2+ influx and is associated with reduced focal adhesion turnover, cell migration, and metastasis formation in vivo. Expression of constitutively active Ras or Rac in these cells partially rescues impaired focal adhesion turnover and cell migration induced by inhibition of store-operated Ca2+ entry, implicating possible roles for these small GTPases in Ca2+-dependent cell migration (
      • Feng M.
      • Grice D.M.
      • Faddy H.M.
      • Nguyen N.
      • Leitch S.
      • Wang Y.
      • Muend S.
      • Kenny P.A.
      • Sukumar S.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      • Rao R.
      Store-independent activation of Orai1 by SPCA2 in mammary tumors.
      ). C, in LNCaP human prostate cancer cells, ORAI1 expression is regulated by the androgen receptor (AR), and ORAI1 silencing is associated with resistance to thapsigargin (TG)-, TNFα-, cisplatin-, and oxaliplatin-induced apoptosis (
      • Flourakis M.
      • Lehen'kyi V.
      • Beck B.
      • Raphaël M.
      • Vandenberghe M.
      • Abeele F.V.
      • Roudbaraki M.
      • Lepage G.
      • Mauroy B.
      • Romanin C.
      • Shuba Y.
      • Skryma R.
      • Prevarskaya N.
      Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.
      ). In A and B (black), ORAI1 expression may promote carcinogenesis; in C (red), ORAI1 expression may inhibit carcinogenesis (i.e. promote apoptosis). IP3Rs, inositol 1,4,5-trisphosphate receptors.
      Although not a focus of this minireview, voltage-gated calcium channels are increasingly studied in cancer, and in many cases, the studies have examined the reasons for changes in expression levels in cancer. This is particularly illustrated in studies assessing mechanisms of altered expression of voltage-gated ion channels. For example, higher relapse in Wilms tumors is associated with higher DNA copy numbers of the α1-subunit of the voltage-gated Ca2+ channel CACNA1E (
      • Natrajan R.
      • Little S.E.
      • Reis-Filho J.S.
      • Hing L.
      • Messahel B.
      • Grundy P.E.
      • Dome J.S.
      • Schneider T.
      • Vujanic G.M.
      • Pritchard-Jones K.
      • Jones C.
      Amplification and overexpression of CACNA1E correlates with relapse in favorable histology Wilms tumors.
      ), and reduced expression of CACNA2D3 via promoter hypermethylation is associated with poor prognosis in gastric cancer (
      • Wanajo A.
      • Sasaki A.
      • Nagasaki H.
      • Shimada S.
      • Otsubo T.
      • Owaki S.
      • Shimizu Y.
      • Eishi Y.
      • Kojima K.
      • Nakajima Y.
      • Kawano T.
      • Yuasa Y.
      • Akiyama Y.
      Methylation of the calcium channel-related gene CACNA2D3 is frequent and a poor prognostic factor in gastric cancer.
      ). These methodological approaches will be applied to other channels and pumps and other cancers in the future.

      Ca2+ Efflux in Cancer

      Ca2+ efflux across the plasma membrane can be mediated by both Na+/Ca2+ exchangers and primary active transport via plasma membrane Ca2+-ATPases (PMCAs). However, most studies of Ca2+ efflux pathways in cancer cells have focused on the latter mechanism. PMCAs are encoded by four genes (PMCA1–4), which are alternatively spliced to generate a suite of Ca2+ efflux pumps responsible for maintaining resting cytosolic free Ca2+ at low (∼100 nm) levels (
      • Strehler E.E.
      • Zacharias D.A.
      Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps.
      ,
      • Brini M.
      • Carafoli E.
      Calcium pumps in health and disease.
      ). PMCAs also contribute to specific cell functions, such as the transport of Ca2+ into milk through PMCA2 (
      • Reinhardt T.A.
      • Lippolis J.D.
      • Shull G.E.
      • Horst R.L.
      Null mutation in the gene encoding plasma membrane Ca2+-ATPase isoform 2 impairs calcium transport into milk.
      ).
      An area in which PMCAs may be critically important in cancer is the regulation of cell death, as reflected in early work assessing the consequences of PMCA overexpression. Overexpression of some PMCA isoforms in CHO cells reduces Ca2+ levels within the endoplasmic reticulum and also attenuates mitochondrial Ca2+ accumulation after cell activation (
      • Brini M.
      • Coletto L.
      • Pierobon N.
      • Kraev N.
      • Guerini D.
      • Carafoli E.
      A comparative functional analysis of plasma membrane Ca2+ pump isoforms in intact cells.
      ), a consequence that would be hypothesized to result in anti-apoptotic effects. Indeed, the overexpression of PMCA in HeLa cells increases their resistance to cell death induced by ceramide (
      • Pinton P.
      • Ferrari D.
      • Rapizzi E.
      • Di Virgilio F.
      • Pozzan T.
      • Rizzuto R.
      The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action.
      ). Recent studies in T47D breast cancer cells show that the overexpression of PMCA2 reduces the degree of cell death induced by ionomycin, and this is associated with a reduction in the duration and magnitude of increases in cytosolic [Ca2+] mediated by this Ca2+ ionophore (
      • VanHouten J.
      • Sullivan C.
      • Bazinet C.
      • Ryoo T.
      • Camp R.
      • Rimm D.L.
      • Chung G.
      • Wysolmerski J.
      PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer.
      ). PMCA2 is an isoform with reported overexpression in some breast cancer cell lines (
      • Lee W.J.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      Plasma membrane calcium ATPases 2 and 4 in human breast cancer cell lines.
      ) and in clinical human samples, in which high levels appear to be associated with a poor prognosis in some patient groups (
      • VanHouten J.
      • Sullivan C.
      • Bazinet C.
      • Ryoo T.
      • Camp R.
      • Rimm D.L.
      • Chung G.
      • Wysolmerski J.
      PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer.
      ). Collectively, these studies suggest that the remodeling of calcium efflux associated with increases in PMCA expression contributes to the acquisition of an anti-apoptotic phenotype in cancer cells.
      Studies assessing the expression of PMCA isoforms during the differentiation of colon cancer cells suggest that a remodeling of PMCA isoform expression is not confined to cancers of the breast. PMCA1 expression remains fairly constant during differentiation of human colon cancer cell lines, whereas PMCA4 undergoes a pronounced increase in expression with differentiation (
      • Ribiczey P.
      • Tordai A.
      • Andrikovics H.
      • Filoteo A.G.
      • Penniston J.T.
      • Enouf J.
      • Enyedi A.
      • Papp B.
      • Kovács T.
      Isoform-specific up-regulation of plasma membrane Ca2+-ATPase expression during colon and gastric cancer cell differentiation.
      ,
      • Aung C.S.
      • Kruger W.A.
      • Poronnik P.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      Plasma membrane Ca2+-ATPase expression during colon cancer cell line differentiation.
      ). PMCA4 overexpression studies in HT29 colon cancer cells suggest that the down-regulation of PMCA4 in colon cancer may help to augment cytosolic Ca2+ responses to proliferative stimuli without sufficiently increasing cytosolic [Ca2+] to levels that promote apoptosis (
      • Aung C.S.
      • Ye W.
      • Plowman G.
      • Peters A.A.
      • Monteith G.R.
      • Roberts-Thomson S.J.
      Plasma membrane calcium ATPase 4 and the remodeling of calcium homeostasis in human colon cancer cells.
      ). The changes in PMCA4 expression seen in the differentiation models correlate well with human colon cancer clinical samples, in which PMCA4 mRNA is reduced in colon adenocarcinomas compared with normal colon (
      • Aung C.S.
      • Ye W.
      • Plowman G.
      • Peters A.A.
      • Monteith G.R.
      • Roberts-Thomson S.J.
      Plasma membrane calcium ATPase 4 and the remodeling of calcium homeostasis in human colon cancer cells.
      ). The up-regulation of PMCA2 expression in breast cancer and the down-regulation of PMCA4 in colon cancer may seem to conflict; however, in both cases, the changes in PMCA expression appear to bestow an advantage to the cancer cell. In the case of PMCA2, this appears to be related to the acquisition of greater resistance to cell death in breast cancer cells, and for PMCA4 augmented responses to proliferative signals in colon cancer cells.

      Intracellular Organelle Ca2+ Channels and Pumps and Cancer

      Intracellular organelles play critical roles in Ca2+-regulated processes either through the regulation of cytosolic free Ca2+ or through modulation of Ca2+-regulated proteins that reside within the organelle. We will outline examples of Ca2+ channels and pumps of the endoplasmic reticulum and Golgi, as these have been the most studied in cancer. However, the recent identification of proteins that play major roles in mitochondrial Ca2+ influx and efflux (
      • De Stefani D.
      • Raffaello A.
      • Teardo E.
      • Szabò I.
      • Rizzuto R.
      A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.
      ,
      • Palty R.
      • Silverman W.F.
      • Hershfinkel M.
      • Caporale T.
      • Sensi S.L.
      • Parnis J.
      • Nolte C.
      • Fishman D.
      • Shoshan-Barmatz V.
      • Herrmann S.
      • Khananshvili D.
      • Sekler I.
      NCLX is an essential component of mitochondrial Na+/Ca2+ exchange.
      ,
      • Drago I.
      • Pizzo P.
      • Pozzan T.
      After half a century mitochondrial calcium in- and efflux machineries reveal themselves.
      ) and the recently identified two-pore channel proteins present in endosomes (TPC1) and lysosomes (TPC2) (
      • Zhu M.X.
      • Ma J.
      • Parrington J.
      • Calcraft P.J.
      • Galione A.
      • Evans A.M.
      Calcium signaling via two-pore channels: local or global, that is the question.
      ) represent new opportunities to improve our understanding of the remodeling of Ca2+ signaling in some cancers and will no doubt be the focus of research in the future (
      • Wenner C.E.
      Targeting mitochondria as a therapeutic target in cancer.
      ).

      Regulators of Endoplasmic Reticulum Ca2+ Levels

      One of the earliest links between the regulation of endoplasmic reticulum Ca2+ and cancer comes from studies of the anti-apoptotic protein Bcl-2 (B cell lymphoma-2). In addition to its early and now well established role in inhibiting the release of the pro-apoptotic factor cytochrome c (
      • Cotter T.G.
      Apoptosis and cancer: the genesis of a research field.
      ,
      • Cory S.
      • Adams J.M.
      The Bcl-2 family: regulators of the cellular life-or-death switch.
      ,
      • Yang J.
      • Liu X.
      • Bhalla K.
      • Kim C.N.
      • Ibrado A.M.
      • Cai J.
      • Peng T.I.
      • Jones D.P.
      • Wang X.
      Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.
      ), Bcl-2 decreases the Ca2+ content of the endoplasmic reticulum (
      • Pinton P.
      • Ferrari D.
      • Rapizzi E.
      • Di Virgilio F.
      • Pozzan T.
      • Rizzuto R.
      The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action.
      ,
      • Pinton P.
      • Ferrari D.
      • Magalhães P.
      • Schulze-Osthoff K.
      • Di Virgilio F.
      • Pozzan T.
      • Rizzuto R.
      Reduced loading of intracellular Ca2+ stores and down-regulation of capacitative Ca2+ influx in Bcl-2-overexpressing cells.
      ,
      • Palmer A.E.
      • Jin C.
      • Reed J.C.
      • Tsien R.Y.
      Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor.
      ). Mechanistically, this occurs at least in part through interaction with the inositol 1,4,5-trisphosphate receptor (
      • Rong Y.P.
      • Aromolaran A.S.
      • Bultynck G.
      • Zhong F.
      • Li X.
      • McColl K.
      • Matsuyama S.
      • Herlitze S.
      • Roderick H.L.
      • Bootman M.D.
      • Mignery G.A.
      • Parys J.B.
      • De Smedt H.
      • Distelhorst C.W.
      Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2 inhibition of apoptotic calcium signals.
      ), likely reducing the ability to achieve the high Ca2+ loads required for mitochondria to accumulate Ca2+ sufficiently to trigger apoptotic cell death (
      • Giacomello M.
      • Drago I.
      • Pizzo P.
      • Pozzan T.
      Mitochondrial Ca2+ as a key regulator of cell life and death.
      ). Some examples of alterations in the expression of key calcium channels and pumps of the endoplasmic reticulum are highlighted in Table 1. Similar to increases in the expression of PMCA4 during colon cancer cell line differentiation and the down-regulation of PMCA4 expression in some colon cancers, SERCA3 pump expression increases with the differentiation of colon cell lines and is down-regulated in colon cancer (
      • Gélébart P.
      • Kovács T.
      • Brouland J.P.
      • van Gorp R.
      • Grossmann J.
      • Rivard N.
      • Panis Y.
      • Martin V.
      • Bredoux R.
      • Enouf J.
      • Papp B.
      Expression of endomembrane calcium pumps in colon and gastric cancer cells. Induction of SERCA3 expression during differentiation.
      ), implicating a major remodeling of active Ca2+ transport in colon cancer. The significance of the down-regulation of SERCA3 is not restricted to colon cancer given the more recent report of a significant down-regulation of SERCA3 in breast cancers, an event that is even seen in benign lesions (
      • Papp B.
      • Brouland J.P.
      Altered endoplasmic reticulum calcium pump expression during breast tumorigenesis.
      ). Further evidence of the potential significance of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) down-regulation in cancer is reflected in studies of mice haplodeficient for SERCA2 (
      • Prasad V.
      • Boivin G.P.
      • Miller M.L.
      • Liu L.H.
      • Erwin C.R.
      • Warner B.W.
      • Shull G.E.
      Haploinsufficiency of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump, predisposes mice to squamous cell tumors via a novel mode of cancer susceptibility.
      ,
      • Liu L.H.
      • Boivin G.P.
      • Prasad V.
      • Periasamy M.
      • Shull G.E.
      Squamous cell tumors in mice heterozygous for a null allele of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump.
      ). These mice are characterized by increased incidence of squamous cell tumors, the mechanism of which likely involves altered Ca2+ signaling and a subsequent change in the microenvironment of skin epithelia (
      • Prasad V.
      • Boivin G.P.
      • Miller M.L.
      • Liu L.H.
      • Erwin C.R.
      • Warner B.W.
      • Shull G.E.
      Haploinsufficiency of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump, predisposes mice to squamous cell tumors via a novel mode of cancer susceptibility.
      ).

      Regulators of Golgi Ca2+ Levels

      Although more recently identified and less widely studied in the context of contributions to cellular processes than SERCAs, secretory pathway Ca2+-ATPases (SPCAs), both the ubiquitously expressed SPCA1 isoform and the more restricted SPCA2 isoform (
      • Xiang M.
      • Mohamalawari D.
      • Rao R.
      A novel isoform of the secretory pathway Ca2+,Mn2+-ATPase, hSPCA2, has unusual properties and is expressed in the brain.
      ,
      • Van Baelen K.
      • Dode L.
      • Vanoevelen J.
      • Callewaert G.
      • De Smedt H.
      • Missiaen L.
      • Parys J.B.
      • Raeymaekers L.
      • Wuytack F.
      The Ca2+/Mn2+ pumps in the Golgi apparatus.
      ), are beginning to be assessed in cancer cells. In MDA-MB-231 basal-like breast cancer cells (which do not express the SPCA2 isoform), SPCA1 silencing inhibits proliferation without changes in global cytosolic [Ca2+], consistent with the minor role of SPCAs (cf. PMCAs and SERCAs) in contributing to cytosolic [Ca2+] recovery in most cell types (
      • Grice D.M.
      • Vetter I.
      • Faddy H.M.
      • Kenny P.A.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      Golgi calcium pump secretory pathway calcium ATPase 1 (SPCA1) is a key regulator of insulin-like growth factor receptor (IGF1R) processing in the basal-like breast cancer cell line MDA-MB-231.
      ). Instead, as may be the case for other Ca2+ channels and pumps located on the membranes of intracellular organelles, the mechanism by which SPCA1 silencing inhibits proliferation may involve alterations in the Ca2+ levels within the Golgi lumen, where Ca2+-regulated enzymes reside. Indeed, one consequence of SPCA1 silencing in MDA-MB-231 breast cancer cells is the inhibition of cleavage of the pro-insulin-like growth factor 1 receptor likely through reduced activity of the Ca2+-sensitive proprotein convertase furin (
      • Grice D.M.
      • Vetter I.
      • Faddy H.M.
      • Kenny P.A.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      Golgi calcium pump secretory pathway calcium ATPase 1 (SPCA1) is a key regulator of insulin-like growth factor receptor (IGF1R) processing in the basal-like breast cancer cell line MDA-MB-231.
      ). The consequences of reduced SPCA1-mediated Ca2+ sequestration may be cell type- and context-dependent as shown by the increased susceptibility of Spca1+/− mice to develop squamous skin tumors (
      • Okunade G.W.
      • Miller M.L.
      • Azhar M.
      • Andringa A.
      • Sanford L.P.
      • Doetschman T.
      • Prasad V.
      • Shull G.E.
      Loss of the Atp2c1 secretory pathway Ca2+-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes.
      ).
      One of the proposed roles for the other SPCA isoform, SPCA2, has been the sequestration of Ca2+ during lactation (
      • Faddy H.M.
      • Smart C.E.
      • Xu R.
      • Lee G.Y.
      • Kenny P.A.
      • Feng M.
      • Rao R.
      • Brown M.A.
      • Bissell M.J.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      Localization of plasma membrane and secretory calcium pumps in the mammary gland.
      ); however, this pump also appears to play a role in the pathophysiology of breast cancer. SPCA2 levels are increased in luminal-like breast cancer cell lines and clinical breast cancers belonging to the luminal B and ERBB2 molecular subtypes (
      • Feng M.
      • Grice D.M.
      • Faddy H.M.
      • Nguyen N.
      • Leitch S.
      • Wang Y.
      • Muend S.
      • Kenny P.A.
      • Sukumar S.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      • Rao R.
      Store-independent activation of Orai1 by SPCA2 in mammary tumors.
      ). This may be related to hormonal factors given that, in MCF-7 breast cancer cells, SPCA2 mRNA levels increase with prolactin (
      • Anantamongkol U.
      • Takemura H.
      • Suthiphongchai T.
      • Krishnamra N.
      • Horio Y.
      Regulation of Ca2+ mobilization by prolactin in mammary gland cells: possible role of secretory pathway Ca2+-ATPase type 2.
      ). Silencing of SPCA2 in breast cancer cell lines that overexpress this Ca2+ pump, such as MCF-7 cells, reduces their proliferation, anchorage-independent growth, and growth in vivo (
      • Feng M.
      • Grice D.M.
      • Faddy H.M.
      • Nguyen N.
      • Leitch S.
      • Wang Y.
      • Muend S.
      • Kenny P.A.
      • Sukumar S.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      • Rao R.
      Store-independent activation of Orai1 by SPCA2 in mammary tumors.
      ). However, in contrast to SPCA1 in breast cancer cells, SPCA2 does not appear to contribute to tumor progression through alterations in Ca2+ levels within the Golgi. In a result that was initially counterintuitive, SPCA2 overexpression increases cytosolic basal [Ca2+] rather than decreasing it, as might be expected for a calcium pump that sequesters Ca2+ from the cytoplasm into the Golgi. Overexpression of SPCA2 leads to its localization at the plasma membrane, where it activates ORAI1 channels, the consequence of which is activation of the transcription factor NFAT (nuclear factor of activated T cells; shown in Fig. 1A) (
      • Feng M.
      • Grice D.M.
      • Faddy H.M.
      • Nguyen N.
      • Leitch S.
      • Wang Y.
      • Muend S.
      • Kenny P.A.
      • Sukumar S.
      • Roberts-Thomson S.J.
      • Monteith G.R.
      • Rao R.
      Store-independent activation of Orai1 by SPCA2 in mammary tumors.
      ). SPCA2 overexpression-induced increases in Ca2+ influx across the plasma membrane represent an example in which the contribution that a calcium pump makes to tumor progression is not directly related to its own Ca2+-transporting ability. The ability of SPCA2 to contribute to tumor growth independently of its own Ca2+-transporting ability suggests that pharmacological inhibitors of SPCA2 Ca2+ transport function may be ineffective in breast cancers in which SPCA2 solely contributes to tumor growth through this ORAI1-dependent mechanism and demonstrates the importance of mechanistic studies assessing the contribution of Ca2+ channels and pumps to tumorigenic pathways.

      Calcium Signaling and Cancer: New Horizons

      Major advances have occurred in the last decade in our understanding of how calcium signaling is remodeled in some cancer cells and how specific calcium channels or pumps represent potential new therapeutic targets in oncology. However, there are areas of cancer research where the link between calcium signaling is still relatively unexplored, such as the “emerging hallmarks of cancer” recently described by Hanahan and Weinberg (
      • Hanahan D.
      • Weinberg R.A.
      Hallmarks of cancer: the next generation.
      ). These include cellular energy metabolism reprogramming, whereby cancer cells shift their energy metabolism to glycolysis, a phenomenon first described by Otto Warburg almost a century ago (
      • Hanahan D.
      • Weinberg R.A.
      Hallmarks of cancer: the next generation.
      ,
      • Koppenol W.H.
      • Bounds P.L.
      • Dang C.V.
      Otto Warburg's contributions to current concepts of cancer metabolism.
      ,
      • Gatenby R.A.
      • Gillies R.J.
      Why do cancers have high aerobic glycolysis?.
      ). Further studies on the possible role of Ca2+ signaling in the regulation of glycolysis, the switch to glycolysis, and the use of glycolysis-generated ATP to fuel Ca2+ pumps in cancer cells are required (
      • Amuthan G.
      • Biswas G.
      • Ananadatheerthavarada H.K.
      • Vijayasarathy C.
      • Shephard H.M.
      • Avadhani N.G.
      Mitochondrial stress-induced calcium signaling, phenotypic changes, and invasive behavior in human lung carcinoma A549 cells.
      ,
      • Mankad P.
      • James A.
      • Siriwardena A.K.
      • Elliott A.C.
      • Bruce J.I.
      Insulin protects pancreatic acinar cells from cytosolic calcium overload and inhibition of the plasma membrane calcium pump.
      ). Another aspect of cancer biology where Ca2+ signaling is clearly going to be critical but has not been fully explored is the tumor microenvironment (
      • Hanahan D.
      • Weinberg R.A.
      Hallmarks of cancer: the next generation.
      ). Due to the depth of work in the area of tumor microenvironment, readers are encouraged to consult the numerous reviews on this topic (
      • Bissell M.J.
      • Hines W.C.
      Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression.
      ,
      • Bissell M.J.
      • Labarge M.A.
      Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment?.
      ,
      • Roskelley C.D.
      • Bissell M.J.
      The dominance of the microenvironment in breast and ovarian cancer.
      ). An aspect of the tumor microenvironment where signaling is likely to be particularly significant is cancer-associated fibroblasts, which are in an “activated” state and are in a dynamic signaling interplay with cancer cells (
      • Hanahan D.
      • Weinberg R.A.
      Hallmarks of cancer: the next generation.
      ,
      • Kalluri R.
      • Zeisberg M.
      Fibroblasts in cancer.
      ). Ca2+ may be critical to this signaling, as reflected by the importance of PDGF in the signaling between cervical cancer cells and cancer-associated fibroblasts (
      • Murata T.
      • Mizushima H.
      • Chinen I.
      • Moribe H.
      • Yagi S.
      • Hoffman R.M.
      • Kimura T.
      • Yoshino K.
      • Ueda Y.
      • Enomoto T.
      • Mekada E.
      HB-EGF and PDGF mediate reciprocal interactions of carcinoma cells with cancer-associated fibroblasts to support progression of uterine cervical cancers.
      ) and the ability of PDGF to elevate cytosolic [Ca2+] in other cell types (
      • DeWald D.B.
      • Torabinejad J.
      • Samant R.S.
      • Johnston D.
      • Erin N.
      • Shope J.C.
      • Xie Y.
      • Welch D.R.
      Metastasis suppression by breast cancer metastasis suppressor 1 involves reduction of phosphoinositide signaling in MDA-MB-435 breast carcinoma cells.
      ).

      Conclusions

      Many processes contribute to cancer development, and Ca2+ signaling seems to play a role in many of them. Numerous studies have now established that some cancers are associated with major changes in the expression of specific Ca2+ channels and pumps and that inhibition of some of these proteins inhibits the proliferation and/or metastasis of cancer cells. The next decade will see the role of Ca2+ in cancer further defined and may see agents that specifically target Ca2+ channels or pumps used in cancer therapy.

      Author Profile

      REFERENCES

        • Hanahan D.
        • Weinberg R.A.
        The hallmarks of cancer.
        Cell. 2000; 100: 57-70
        • Roderick H.L.
        • Cook S.J.
        Ca2+ signaling checkpoints in cancer: remodeling Ca2+ for cancer cell proliferation and survival.
        Nat. Rev. Cancer. 2008; 8: 361-375
        • Prevarskaya N.
        • Skryma R.
        • Shuba Y.
        Calcium in tumor metastasis: new roles for known actors.
        Nat. Rev. Cancer. 2011; 11: 609-618
        • Fiorio Pla A.
        • Avanzato D.
        • Munaron L.
        • Ambudkar I.S.
        Ion channels and transporters in cancer. 6. Vascularizing the tumor: TRP channels as molecular targets.
        Am. J. Physiol. Cell Physiol. 2012; 302: C9-C15
        • Rizzuto R.
        • Pinton P.
        • Ferrari D.
        • Chami M.
        • Szabadkai G.
        • Magalhães P.J.
        • Di Virgilio F.
        • Pozzan T.
        Calcium and apoptosis: facts and hypotheses.
        Oncogene. 2003; 22: 8619-8627
        • Lehen'kyi V.
        • Shapovalov G.
        • Skryma R.
        • Prevarskaya N.
        Ion channnels and transporters in cancer. 5. Ion channels in control of cancer and cell apoptosis.
        Am. J. Physiol. Cell Physiol. 2011; 301: C1281-C1289
        • Ramsey I.S.
        • Delling M.
        • Clapham D.E.
        An introduction to TRP channels.
        Annu. Rev. Physiol. 2006; 68: 619-647
        • Tsavaler L.
        • Shapero M.H.
        • Morkowski S.
        • Laus R.
        Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins.
        Cancer Res. 2001; 61: 3760-3769
        • McKemy D.D.
        • Neuhausser W.M.
        • Julius D.
        Identification of a cold receptor reveals a general role for TRP channels in thermosensation.
        Nature. 2002; 416: 52-58
        • Knowlton W.M.
        • Daniels R.L.
        • Palkar R.
        • McCoy D.D.
        • McKemy D.D.
        Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice.
        PLoS ONE. 2011; 6: e25894
        • Zhang L.
        • Barritt G.J.
        Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells.
        Cancer Res. 2004; 64: 8365-8373
        • Monteith G.R.
        • McAndrew D.
        • Faddy H.M.
        • Roberts-Thomson S.J.
        Calcium and cancer: targeting Ca2+ transport.
        Nat. Rev. Cancer. 2007; 7: 519-530
        • Gkika D.
        • Flourakis M.
        • Lemonnier L.
        • Prevarskaya N.
        PSA reduces prostate cancer cell motility by stimulating TRPM8 activity and plasma membrane expression.
        Oncogene. 2010; 29: 4611-4616
        • Bidaux G.
        • Roudbaraki M.
        • Merle C.
        • Crépin A.
        • Delcourt P.
        • Slomianny C.
        • Thebault S.
        • Bonnal J.L.
        • Benahmed M.
        • Cabon F.
        • Mauroy B.
        • Prevarskaya N.
        Evidence for specific TRPM8 expression in human prostate secretory epithelial cells: functional androgen receptor requirement.
        Endocr. Relat. Cancer. 2005; 12: 367-382
        • Bidaux G.
        • Flourakis M.
        • Thebault S.
        • Zholos A.
        • Beck B.
        • Gkika D.
        • Roudbaraki M.
        • Bonnal J.L.
        • Mauroy B.
        • Shuba Y.
        • Skryma R.
        • Prevarskaya N.
        Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function.
        J. Clin. Invest. 2007; 117: 1647-1657
        • Henshall S.M.
        • Afar D.E.
        • Hiller J.
        • Horvath L.G.
        • Quinn D.I.
        • Rasiah K.K.
        • Gish K.
        • Willhite D.
        • Kench J.G.
        • Gardiner-Garden M.
        • Stricker P.D.
        • Scher H.I.
        • Grygiel J.J.
        • Agus D.B.
        • Mack D.H.
        • Sutherland R.L.
        Survival analysis of genome-wide gene expression profiles of prostate cancers identifies new prognostic targets of disease relapse.
        Cancer Res. 2003; 63: 4196-4203
        • Prevarskaya N.
        • Skryma R.
        • Bidaux G.
        • Flourakis M.
        • Shuba Y.
        Ion channels in death and differentiation of prostate cancer cells.
        Cell Death Differ. 2007; 14: 1295-1304
        • Fixemer T.
        • Wissenbach U.
        • Flockerzi V.
        • Bonkhoff H.
        Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression.
        Oncogene. 2003; 22: 7858-7861
        • Lehen'kyi V.
        • Flourakis M.
        • Skryma R.
        • Prevarskaya N.
        TRPV6 channel controls prostate cancer cell proliferation via Ca2+/NFAT-dependent pathways.
        Oncogene. 2007; 26: 7380-7385
        • Wissenbach U.
        • Niemeyer B.A.
        Trpv6.
        Handb. Exp. Pharmacol. 2007; 179: 221-234
        • Bolanz K.A.
        • Hediger M.A.
        • Landowski C.P.
        The role of TRPV6 in breast carcinogenesis.
        Mol. Cancer Ther. 2008; 7: 271-279
        • Aydar E.
        • Yeo S.
        • Djamgoz M.
        • Palmer C.
        Abnormal expression, localization, and interaction of canonical transient receptor potential ion channels in human breast cancer cell lines and tissues: a potential target for breast cancer diagnosis and therapy.
        Cancer Cell Int. 2009; 9: 23
        • Yang S.L.
        • Cao Q.
        • Zhou K.C.
        • Feng Y.J.
        • Wang Y.Z.
        Transient receptor potential channel C3 contributes to the progression of human ovarian cancer.
        Oncogene. 2009; 28: 1320-1328
        • Shi Y.
        • Ding X.
        • He Z.H.
        • Zhou K.C.
        • Wang Q.
        • Wang Y.Z.
        Critical role of TRPC6 channels in G2 phase transition and the development of human esophageal cancer.
        Gut. 2009; 58: 1443-1450
        • Ding X.
        • He Z.
        • Zhou K.
        • Cheng J.
        • Yao H.
        • Lu D.
        • Cai R.
        • Jin Y.
        • Dong B.
        • Xu Y.
        • Wang Y.
        Essential role of TRPC6 channels in G2/M phase transition and development of human glioma.
        J. Natl. Cancer Inst. 2010; 102: 1052-1068
        • Fiorio Pla A.
        • Ong H.L.
        • Cheng K.T.
        • Brossa A.
        • Bussolati B.
        • Lockwich T.
        • Paria B.
        • Munaron L.
        • Ambudkar I.S.
        TRPV4 mediates tumor-derived endothelial cell migration via arachidonic acid-activated actin remodeling.
        Oncogene. 2012; 31: 200-212
        • Wei C.
        • Wang X.
        • Chen M.
        • Ouyang K.
        • Song L.S.
        • Cheng H.
        Calcium flickers steer cell migration.
        Nature. 2009; 457: 901-905
        • Numata T.
        • Shimizu T.
        • Okada Y.
        TRPM7 is a stretch- and swelling-activated cation channel involved in volume regulation in human epithelial cells.
        Am. J. Physiol. Cell Physiol. 2007; 292: C460-C467
        • Rybarczyk P.
        • Gautier M.
        • Hague F.
        • Dhennin-Duthille I.
        • Chatelain D.
        • Kerr-Conte J.
        • Pattou F.
        • Regimbeau J.M.
        • Sevestre H.
        • Ouadid-Ahidouch H.
        Transient receptor potential melastatin-related 7 channel is overexpressed in human pancreatic ductal adenocarcinomas and regulates human pancreatic cancer cell migration.
        Int. J. Cancer. 2012; 131: E851-E861
        • Gao H.
        • Chen X.
        • Du X.
        • Guan B.
        • Liu Y.
        • Zhang H.
        EGF enhances the migration of cancer cells by up-regulation of TRPM7.
        Cell Calcium. 2011; 50: 559-568
        • Chen J.P.
        • Luan Y.
        • You C.X.
        • Chen X.H.
        • Luo R.C.
        • Li R.
        TRPM7 regulates the migration of human nasopharyngeal carcinoma cell by mediating Ca2+ influx.
        Cell Calcium. 2010; 47: 425-432
        • Parekh A.B.
        • Putney Jr., J.W.
        Store-operated calcium channels.
        Physiol. Rev. 2005; 85: 757-810
        • Roberts-Thomson S.J.
        • Peters A.A.
        • Grice D.M.
        • Monteith G.R.
        ORAI-mediated calcium entry: mechanism and roles, diseases and pharmacology.
        Pharmacol. Ther. 2010; 127: 121-130
        • Hogan P.G.
        • Rao A.
        Dissecting ICRAC, a store-operated calcium current.
        Trends Biochem. Sci. 2007; 32: 235-245
        • Feske S.
        • Gwack Y.
        • Prakriya M.
        • Srikanth S.
        • Puppel S.H.
        • Tanasa B.
        • Hogan P.G.
        • Lewis R.S.
        • Daly M.
        • Rao A.
        A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function.
        Nature. 2006; 441: 179-185
        • Roos J.
        • DiGregorio P.J.
        • Yeromin A.V.
        • Ohlsen K.
        • Lioudyno M.
        • Zhang S.
        • Safrina O.
        • Kozak J.A.
        • Wagner S.L.
        • Cahalan M.D.
        • Veliçelebi G.
        • Stauderman K.A.
        STIM1, an essential and conserved component of store-operated Ca2+ channel function.
        J. Cell Biol. 2005; 169: 435-445
        • McAndrew D.
        • Grice D.M.
        • Peters A.A.
        • Davis F.M.
        • Stewart T.
        • Rice M.
        • Smart C.E.
        • Brown M.A.
        • Kenny P.A.
        • Roberts-Thomson S.J.
        • Monteith G.R.
        ORAI1-mediated calcium influx in lactation and in breast cancer.
        Mol. Cancer Ther. 2011; 10: 448-460
        • Yang S.
        • Zhang J.J.
        • Huang X.Y.
        Orai1 and STIM1 are critical for breast tumor cell migration and metastasis.
        Cancer Cell. 2009; 15: 124-134
        • Feng M.
        • Grice D.M.
        • Faddy H.M.
        • Nguyen N.
        • Leitch S.
        • Wang Y.
        • Muend S.
        • Kenny P.A.
        • Sukumar S.
        • Roberts-Thomson S.J.
        • Monteith G.R.
        • Rao R.
        Store-independent activation of Orai1 by SPCA2 in mammary tumors.
        Cell. 2010; 143: 84-98
        • Chen Y.F.
        • Chiu W.T.
        • Chen Y.T.
        • Lin P.Y.
        • Huang H.J.
        • Chou C.Y.
        • Chang H.C.
        • Tang M.J.
        • Shen M.R.
        Calcium store sensor stromal interaction molecule 1-dependent signaling plays an important role in cervical cancer growth, migration, and angiogenesis.
        Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 15225-15230
        • Motiani R.K.
        • Abdullaev I.F.
        • Trebak M.
        A novel native store-operated calcium channel encoded by Orai3: selective requirement of Orai3 versus Orai1 in estrogen receptor-positive versus estrogen receptor-negative breast cancer cells.
        J. Biol. Chem. 2010; 285: 19173-19183
        • Faouzi M.
        • Hague F.
        • Potier M.
        • Ahidouch A.
        • Sevestre H.
        • Ouadid-Ahidouch H.
        Down-regulation of Orai3 arrests cell cycle progression and induces apoptosis in breast cancer cells but not in normal breast epithelial cells.
        J. Cell. Physiol. 2011; 226: 542-551
        • Flourakis M.
        • Lehen'kyi V.
        • Beck B.
        • Raphaël M.
        • Vandenberghe M.
        • Abeele F.V.
        • Roudbaraki M.
        • Lepage G.
        • Mauroy B.
        • Romanin C.
        • Shuba Y.
        • Skryma R.
        • Prevarskaya N.
        Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.
        Cell Death Dis. 2010; 1: e75
        • Natrajan R.
        • Little S.E.
        • Reis-Filho J.S.
        • Hing L.
        • Messahel B.
        • Grundy P.E.
        • Dome J.S.
        • Schneider T.
        • Vujanic G.M.
        • Pritchard-Jones K.
        • Jones C.
        Amplification and overexpression of CACNA1E correlates with relapse in favorable histology Wilms tumors.
        Clin. Cancer Res. 2006; 12: 7284-7293
        • Wanajo A.
        • Sasaki A.
        • Nagasaki H.
        • Shimada S.
        • Otsubo T.
        • Owaki S.
        • Shimizu Y.
        • Eishi Y.
        • Kojima K.
        • Nakajima Y.
        • Kawano T.
        • Yuasa Y.
        • Akiyama Y.
        Methylation of the calcium channel-related gene CACNA2D3 is frequent and a poor prognostic factor in gastric cancer.
        Gastroenterology. 2008; 135: 580-590
        • Strehler E.E.
        • Zacharias D.A.
        Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps.
        Physiol. Rev. 2001; 81: 21-50
        • Brini M.
        • Carafoli E.
        Calcium pumps in health and disease.
        Physiol. Rev. 2009; 89: 1341-1378
        • Reinhardt T.A.
        • Lippolis J.D.
        • Shull G.E.
        • Horst R.L.
        Null mutation in the gene encoding plasma membrane Ca2+-ATPase isoform 2 impairs calcium transport into milk.
        J. Biol. Chem. 2004; 279: 42369-42373
        • Brini M.
        • Coletto L.
        • Pierobon N.
        • Kraev N.
        • Guerini D.
        • Carafoli E.
        A comparative functional analysis of plasma membrane Ca2+ pump isoforms in intact cells.
        J. Biol. Chem. 2003; 278: 24500-24508
        • Pinton P.
        • Ferrari D.
        • Rapizzi E.
        • Di Virgilio F.
        • Pozzan T.
        • Rizzuto R.
        The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action.
        EMBO J. 2001; 20: 2690-2701
        • VanHouten J.
        • Sullivan C.
        • Bazinet C.
        • Ryoo T.
        • Camp R.
        • Rimm D.L.
        • Chung G.
        • Wysolmerski J.
        PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer.
        Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 11405-11410
        • Lee W.J.
        • Roberts-Thomson S.J.
        • Monteith G.R.
        Plasma membrane calcium ATPases 2 and 4 in human breast cancer cell lines.
        Biochem. Biophys. Res. Commun. 2005; 337: 779-783
        • Ribiczey P.
        • Tordai A.
        • Andrikovics H.
        • Filoteo A.G.
        • Penniston J.T.
        • Enouf J.
        • Enyedi A.
        • Papp B.
        • Kovács T.
        Isoform-specific up-regulation of plasma membrane Ca2+-ATPase expression during colon and gastric cancer cell differentiation.
        Cell Calcium. 2007; 42: 590-605
        • Aung C.S.
        • Kruger W.A.
        • Poronnik P.
        • Roberts-Thomson S.J.
        • Monteith G.R.
        Plasma membrane Ca2+-ATPase expression during colon cancer cell line differentiation.
        Biochem. Biophys. Res. Commun. 2007; 355: 932-936
        • Aung C.S.
        • Ye W.
        • Plowman G.
        • Peters A.A.
        • Monteith G.R.
        • Roberts-Thomson S.J.
        Plasma membrane calcium ATPase 4 and the remodeling of calcium homeostasis in human colon cancer cells.
        Carcinogenesis. 2009; 30: 1962-1969
        • De Stefani D.
        • Raffaello A.
        • Teardo E.
        • Szabò I.
        • Rizzuto R.
        A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.
        Nature. 2011; 476: 336-340
        • Palty R.
        • Silverman W.F.
        • Hershfinkel M.
        • Caporale T.
        • Sensi S.L.
        • Parnis J.
        • Nolte C.
        • Fishman D.
        • Shoshan-Barmatz V.
        • Herrmann S.
        • Khananshvili D.
        • Sekler I.
        NCLX is an essential component of mitochondrial Na+/Ca2+ exchange.
        Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 436-441
        • Drago I.
        • Pizzo P.
        • Pozzan T.
        After half a century mitochondrial calcium in- and efflux machineries reveal themselves.
        EMBO J. 2011; 30: 4119-4125
        • Zhu M.X.
        • Ma J.
        • Parrington J.
        • Calcraft P.J.
        • Galione A.
        • Evans A.M.
        Calcium signaling via two-pore channels: local or global, that is the question.
        Am. J. Physiol. Cell Physiol. 2010; 298: C430-C441
        • Wenner C.E.
        Targeting mitochondria as a therapeutic target in cancer.
        J. Cell. Physiol. 2012; 227: 450-456
        • Cotter T.G.
        Apoptosis and cancer: the genesis of a research field.
        Nat. Rev. Cancer. 2009; 9: 501-507
        • Cory S.
        • Adams J.M.
        The Bcl-2 family: regulators of the cellular life-or-death switch.
        Nat. Rev. Cancer. 2002; 2: 647-656
        • Yang J.
        • Liu X.
        • Bhalla K.
        • Kim C.N.
        • Ibrado A.M.
        • Cai J.
        • Peng T.I.
        • Jones D.P.
        • Wang X.
        Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.
        Science. 1997; 275: 1129-1132
        • Pinton P.
        • Ferrari D.
        • Magalhães P.
        • Schulze-Osthoff K.
        • Di Virgilio F.
        • Pozzan T.
        • Rizzuto R.
        Reduced loading of intracellular Ca2+ stores and down-regulation of capacitative Ca2+ influx in Bcl-2-overexpressing cells.
        J. Cell Biol. 2000; 148: 857-862
        • Palmer A.E.
        • Jin C.
        • Reed J.C.
        • Tsien R.Y.
        Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor.
        Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 17404-17409
        • Rong Y.P.
        • Aromolaran A.S.
        • Bultynck G.
        • Zhong F.
        • Li X.
        • McColl K.
        • Matsuyama S.
        • Herlitze S.
        • Roderick H.L.
        • Bootman M.D.
        • Mignery G.A.
        • Parys J.B.
        • De Smedt H.
        • Distelhorst C.W.
        Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2 inhibition of apoptotic calcium signals.
        Mol. Cell. 2008; 31: 255-265
        • Giacomello M.
        • Drago I.
        • Pizzo P.
        • Pozzan T.
        Mitochondrial Ca2+ as a key regulator of cell life and death.
        Cell Death Differ. 2007; 14: 1267-1274
        • Gélébart P.
        • Kovács T.
        • Brouland J.P.
        • van Gorp R.
        • Grossmann J.
        • Rivard N.
        • Panis Y.
        • Martin V.
        • Bredoux R.
        • Enouf J.
        • Papp B.
        Expression of endomembrane calcium pumps in colon and gastric cancer cells. Induction of SERCA3 expression during differentiation.
        J. Biol. Chem. 2002; 277: 26310-26320
        • Papp B.
        • Brouland J.P.
        Altered endoplasmic reticulum calcium pump expression during breast tumorigenesis.
        Breast Cancer. 2011; 5: 163-174
        • Prasad V.
        • Boivin G.P.
        • Miller M.L.
        • Liu L.H.
        • Erwin C.R.
        • Warner B.W.
        • Shull G.E.
        Haploinsufficiency of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump, predisposes mice to squamous cell tumors via a novel mode of cancer susceptibility.
        Cancer Res. 2005; 65: 8655-8661
        • Liu L.H.
        • Boivin G.P.
        • Prasad V.
        • Periasamy M.
        • Shull G.E.
        Squamous cell tumors in mice heterozygous for a null allele of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump.
        J. Biol. Chem. 2001; 276: 26737-26740
        • Xiang M.
        • Mohamalawari D.
        • Rao R.
        A novel isoform of the secretory pathway Ca2+,Mn2+-ATPase, hSPCA2, has unusual properties and is expressed in the brain.
        J. Biol. Chem. 2005; 280: 11608-11614
        • Van Baelen K.
        • Dode L.
        • Vanoevelen J.
        • Callewaert G.
        • De Smedt H.
        • Missiaen L.
        • Parys J.B.
        • Raeymaekers L.
        • Wuytack F.
        The Ca2+/Mn2+ pumps in the Golgi apparatus.
        Biochim. Biophys. Acta. 2004; 1742: 103-112
        • Grice D.M.
        • Vetter I.
        • Faddy H.M.
        • Kenny P.A.
        • Roberts-Thomson S.J.
        • Monteith G.R.
        Golgi calcium pump secretory pathway calcium ATPase 1 (SPCA1) is a key regulator of insulin-like growth factor receptor (IGF1R) processing in the basal-like breast cancer cell line MDA-MB-231.
        J. Biol. Chem. 2010; 285: 37458-37466
        • Okunade G.W.
        • Miller M.L.
        • Azhar M.
        • Andringa A.
        • Sanford L.P.
        • Doetschman T.
        • Prasad V.
        • Shull G.E.
        Loss of the Atp2c1 secretory pathway Ca2+-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes.
        J. Biol. Chem. 2007; 282: 26517-26527
        • Faddy H.M.
        • Smart C.E.
        • Xu R.
        • Lee G.Y.
        • Kenny P.A.
        • Feng M.
        • Rao R.
        • Brown M.A.
        • Bissell M.J.
        • Roberts-Thomson S.J.
        • Monteith G.R.
        Localization of plasma membrane and secretory calcium pumps in the mammary gland.
        Biochem. Biophys. Res. Commun. 2008; 369: 977-981
        • Anantamongkol U.
        • Takemura H.
        • Suthiphongchai T.
        • Krishnamra N.
        • Horio Y.
        Regulation of Ca2+ mobilization by prolactin in mammary gland cells: possible role of secretory pathway Ca2+-ATPase type 2.
        Biochem. Biophys. Res. Commun. 2007; 352: 537-542
        • Hanahan D.
        • Weinberg R.A.
        Hallmarks of cancer: the next generation.
        Cell. 2011; 144: 646-674
        • Koppenol W.H.
        • Bounds P.L.
        • Dang C.V.
        Otto Warburg's contributions to current concepts of cancer metabolism.
        Nat. Rev. Cancer. 2011; 11: 325-337
        • Gatenby R.A.
        • Gillies R.J.
        Why do cancers have high aerobic glycolysis?.
        Nat. Rev. Cancer. 2004; 4: 891-899
        • Amuthan G.
        • Biswas G.
        • Ananadatheerthavarada H.K.
        • Vijayasarathy C.
        • Shephard H.M.
        • Avadhani N.G.
        Mitochondrial stress-induced calcium signaling, phenotypic changes, and invasive behavior in human lung carcinoma A549 cells.
        Oncogene. 2002; 21: 7839-7849
        • Mankad P.
        • James A.
        • Siriwardena A.K.
        • Elliott A.C.
        • Bruce J.I.
        Insulin protects pancreatic acinar cells from cytosolic calcium overload and inhibition of the plasma membrane calcium pump.
        J. Biol. Chem. 2012; 287: 1823-1836
        • Bissell M.J.
        • Hines W.C.
        Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression.
        Nat. Med. 2011; 17: 320-329
        • Bissell M.J.
        • Labarge M.A.
        Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment?.
        Cancer Cell. 2005; 7: 17-23
        • Roskelley C.D.
        • Bissell M.J.
        The dominance of the microenvironment in breast and ovarian cancer.
        Semin. Cancer Biol. 2002; 12: 97-104
        • Kalluri R.
        • Zeisberg M.
        Fibroblasts in cancer.
        Nat. Rev. Cancer. 2006; 6: 392-401
        • Murata T.
        • Mizushima H.
        • Chinen I.
        • Moribe H.
        • Yagi S.
        • Hoffman R.M.
        • Kimura T.
        • Yoshino K.
        • Ueda Y.
        • Enomoto T.
        • Mekada E.
        HB-EGF and PDGF mediate reciprocal interactions of carcinoma cells with cancer-associated fibroblasts to support progression of uterine cervical cancers.
        Cancer Res. 2011; 71: 6633-6642
        • DeWald D.B.
        • Torabinejad J.
        • Samant R.S.
        • Johnston D.
        • Erin N.
        • Shope J.C.
        • Xie Y.
        • Welch D.R.
        Metastasis suppression by breast cancer metastasis suppressor 1 involves reduction of phosphoinositide signaling in MDA-MB-435 breast carcinoma cells.
        Cancer Res. 2005; 65: 713-717
        • Dhennin-Duthille I.
        • Gautier M.
        • Faouzi M.
        • Guilbert A.
        • Brevet M.
        • Vaudry D.
        • Ahidouch A.
        • Sevestre H.
        • Ouadid-Ahidouch H.
        High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters.
        Cell. Physiol. Biochem. 2011; 28: 813-822
        • El Boustany C.
        • Bidaux G.
        • Enfissi A.
        • Delcourt P.
        • Prevarskaya N.
        • Capiod T.
        Capacitative calcium entry and transient receptor potential canonical 6 expression control human hepatoma cell proliferation.
        Hepatology. 2008; 47: 2068-2077
        • Yee N.S.
        • Zhou W.
        • Lee M.
        Transient receptor potential channel TRPM8 is overexpressed and required for cellular proliferation in pancreatic adenocarcinoma.
        Cancer Lett. 2010; 297: 49-55
        • Schmidt U.
        • Fuessel S.
        • Koch R.
        • Baretton G.B.
        • Lohse A.
        • Tomasetti S.
        • Unversucht S.
        • Froehner M.
        • Wirth M.P.
        • Meye A.
        Quantitative multigene expression profiling of primary prostate cancer.
        Prostate. 2006; 66: 1521-1534
        • Kalogris C.
        • Caprodossi S.
        • Amantini C.
        • Lambertucci F.
        • Nabissi M.
        • Morelli M.B.
        • Farfariello V.
        • Filosa A.
        • Emiliozzi M.C.
        • Mammana G.
        • Santoni G.
        Expression of transient receptor potential vanilloid-1 (TRPV1) in urothelial cancers of human bladder: relation to clinicopathological and molecular parameters.
        Histopathology. 2010; 57: 744-752
        • Czifra G.
        • Varga A.
        • Nyeste K.
        • Marincsák R.
        • Tóth B.I.
        • Kovács I.
        • Kovács L.
        • Bíró T.
        Increased expressions of cannabinoid receptor-1 and transient receptor potential vanilloid-1 in human prostate carcinoma.
        J. Cancer Res. Clin. Oncol. 2009; 135: 507-514
        • Zhuang L.
        • Peng J.B.
        • Tou L.
        • Takanaga H.
        • Adam R.M.
        • Hediger M.A.
        • Freeman M.R.
        Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies.
        Lab. Invest. 2002; 82: 1755-1764
        • Wang X.T.
        • Nagaba Y.
        • Cross H.S.
        • Wrba F.
        • Zhang L.
        • Guggino S.E.
        The mRNA of L-type calcium channel elevated in colon cancer: protein distribution in normal and cancerous colon.
        Am. J. Pathol. 2000; 157: 1549-1562
        • Gackière F.
        • Bidaux G.
        • Delcourt P.
        • Van Coppenolle F.
        • Katsogiannou M.
        • Dewailly E.
        • Bavencoffe A.
        • Van Chuoï-Mariot M.T.
        • Mauroy B.
        • Prevarskaya N.
        • Mariot P.
        CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells.
        J. Biol. Chem. 2008; 283: 10162-10173
        • Kang S.S.
        • Han K.S.
        • Ku B.M.
        • Lee Y.K.
        • Hong J.
        • Shin H.Y.
        • Almonte A.G.
        • Woo D.H.
        • Brat D.J.
        • Hwang E.M.
        • Yoo S.H.
        • Chung C.K.
        • Park S.H.
        • Paek S.H.
        • Roh E.J.
        • Lee S.J.
        • Park J.Y.
        • Traynelis S.F.
        • Lee C.J.
        Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.
        Cancer Res. 2010; 70: 1173-1183
        • Shibao K.
        • Fiedler M.J.
        • Nagata J.
        • Minagawa N.
        • Hirata K.
        • Nakayama Y.
        • Iwakiri Y.
        • Nathanson M.H.
        • Yamaguchi K.
        The type III inositol 1,4,5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma.
        Cell Calcium. 2010; 48: 315-323
        • Endo Y.
        • Uzawa K.
        • Mochida Y.
        • Shiiba M.
        • Bukawa H.
        • Yokoe H.
        • Tanzawa H.
        Sarco/endoplasmic reticulum Ca2+-ATPase type 2 down-regulated in human oral squamous cell carcinoma.
        Int. J. Cancer. 2004; 110: 225-231