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Sustained Production of H2O2Activates Pro-matrix Metalloproteinase-2 through Receptor Tyrosine Kinases/Phosphatidylinositol 3-Kinase/NF-κB Pathway*

  • Sang-Oh Yoon
    Affiliations
    From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea
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  • Soo-Jin Park
    Affiliations
    From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea
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  • Sun Young Yoon
    Affiliations
    From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea
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  • Chang-Hyun Yun
    Affiliations
    From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea
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  • An-Sik Chung
    Correspondence
    To whom correspondence should be addressed: Dept. of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea. Tel.: 82-42-869-2625; Fax: 82-42-869-2610;
    Affiliations
    From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea
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  • Author Footnotes
    * This work was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (02-PJ1-PG10-20801-0001).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Open AccessPublished:June 10, 2002DOI:https://doi.org/10.1074/jbc.M202647200
      A rate-limiting step of tumor cell metastasis is matrix degradation by active matrix metalloproteinases (MMPs). It is known that reactive oxygen species are involved in tumor metastasis. Sustained production of H2O2 by phenazine methosulfate (PMS) induced activation of pro-MMP-2 through the induction of membrane type 1-MMP (MT1-MMP) expression in HT1080 cells. MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 and -2 levels were changed negligibly by PMS. A one time treatment with H2O2 did not induce activation of MMPs. It was also demonstrated that superoxide anions and hydroxyl radicals were not related to PMS action. PMS-induced pro-MMP-2 activation was regulated by the receptor tyrosine kinases, especially the receptors of platelet-derived growth factor and vascular endothelial growth factor, and downstream on the phosphatidylinositol 3-kinase/NF-κB pathway but not Ras, cAMP-dependent protein kinase, protein kinase C, and mitogen-activated protein kinases. PMS did not induce pro-MMP-2 activation in T98G and NIH3T3 cells. This may be related to a low level of MT1-MMP, indicating a threshold level of MT1-MMP is important for pro-MMP-2 activation. Furthermore, PMS increased cell motility and invasion but decreased cell-cell interaction. Cell-matrix interaction was not affected by PMS.
      ECM
      extracellular matrix
      DDC
      diethyldithiocarbamic acid
      MMP
      matrix metalloproteinase
      MT1-MMP
      membrane-type 1-matrix metalloproteinase
      PDGF
      platelet-derived growth factor
      PMS
      phenazine methosulfate
      TIMP
      tissue inhibitor of matrix metalloproteinase
      DMEM
      Dulbecco's modified Eagle's medium
      PI3-K
      phosphatidylinositol 3-kinase
      PBS
      phosphate-buffered saline
      DCFH-DA
      2′,7′-dichlorofluorescin diacetate
      VEGF
      vascular endothelial growth factor
      ROS
      reactive oxygen species
      SNP
      sodium nitroprusside
      Metastasis is a major cause of death among cancer patients. The metastasis of cancer cells requires several sequential steps, such as changes in cell-ECM1interaction, the disconnection of intercellular adhesions and separation of single cells from solid tumor tissue, a degradation of ECM, the locomotion of tumor cells into the extracellular matrix, the invasion of lymph and blood vessels, immunologic escape in the circulation, adhesion to endothelial cells, extravasation from lymph and blood vessels, proliferation of cells, and the induction of angiogenesis (
      • Liotta L.A.
      • Steeg P.S.
      • Stetler-Stevenson W.G.
      ).
      The main groups of proteolytic enzymes involved in the tumor invasion are matrix metalloproteinases (MMPs). The MMPs, a family of zinc-dependent endopeptidases, are involved in tumor invasion, metastasis, and angiogenesis in cancer (
      • Chang C.
      • Werb Z.
      ,
      • Westermarck J.
      • Kahari V.M.
      ). MMPs are important enzymes for the proteolysis of extracellular matrix proteins such as collagen, proteoglycan, elastin, laminin, and fibronectin (
      • Johnson L.L.
      • Dyer R.
      • Hupe D.J.
      ). MMPs are synthesized as preproenzymes, and most of them are secreted from the cells as proenzymes. Among previously reported human MMPs, MMP-2 (gelatinase A/Mr 72,000 type IV collagenase) and MMP-9 (gelatinase B/Mr 92,000 type IV collagenase) are thought to be key enzymes for degrading type IV collagen, which is a major component of the basement membrane (
      • Westermarck J.
      • Kahari V.M.
      ). Both MMP-2 and MMP-9 are abundantly expressed in various malignant tumors (
      • Johnsen M.
      • Lund L.R.
      • Romer J.
      • Almholt K.
      • Dano K.
      ) and contribute to invasion and metastasis (
      • Liabakk N.B.
      • Talbot I.
      • Smith R.A.
      • Wilkinson K.
      • Balkwill F.
      ).
      Pro-MMP-2 can be activated by several mechanisms dependent on stimulators and cell types. Initially, pro-MMP-2 can be activated by the action of highly expressed MT1-MMP and the adequate expression of TIMP-2 (
      • Sato H.
      • Takino T.
      • Okada Y.
      • Cao J.
      • Shinagawa A.
      • Yamamoto E.
      • Seiki M.
      ,
      • Sternlicht M.D.
      • Werb Z.
      ,
      • Forget M.A.
      • Desrosiers R.R.
      • Beliveau R.
      ). In this situation, the balance between MT1-MMP and TIMP-2 is important. At low concentrations, TIMP-2 binds to the catalytic site of some activated MT1-MMP molecules, generating receptors for pro-MMP-2, thereby promoting MMP-2 activation. In this situation, MT1-MMP forms a homophilic complex through the hemopexin-like domain that acts as a mechanism to keep MT1-MMP molecules close together to facilitate pro-MMP-2 activation (
      • Itoh Y.
      • Takamura A.
      • Ito N.
      • Maru Y.
      • Sato H.
      • Suenaga N.
      • Aoki T.
      • Seiki M.
      ). At high concentrations, TIMP-2 binds and inhibits any active MT1-MMP, thus completely preventing MMP-2 activation. Next, the down-regulation of TIMP-2 by type IV collagen without affecting MT1-MMP can lead to pro-MMP-2 activation (
      • Maquoi E.
      • Frankenne F.
      • Noel A.
      • Krell H.W.
      • Grams F.
      • Foidart J.M.
      ). In this case, pro-MMP-2 activation involved neither a transcriptional modulation of MMP-2, MT1-MMP, or TIMP-2 expression nor any alteration of MT1-MMP protein synthesis or processing. Finally, activation of pro-MMP-2 in fibroblast culture in a type I collagen lattice was induced intracellularly and is associated with Golgi-enriched intracellular membranes without the help of MT1-MMP (
      • Lee A.Y.
      • Akers K.T.
      • Collier M., Li, L.
      • Eisen A.Z.
      • Seltzer J.L.
      ).
      Reactive oxygen species (ROS) are involved in aging and many diseases as follows: cancer, diabetes mellitus, atherosclerosis, neurological degeneration, angiogenesis, and tumor invasion. However, there are few reports on what kinds of ROS and how ROS affect tumor cell invasion. In particular, the specific mechanism of transcriptional regulation of MT1-MMP expression has not yet been understood. Here we report that sustained exposure of H2O2, not a one time exposure of H2O2, to cells increases pro-MMP-2 activation through the induction of MT1-MMP expression, and this activation is mediated via a receptor tyrosine kinases/PI3-kinase/NF-κB activation. The sustained production of H2O2 also increased cell motility and invasion but decreased cell-cell interaction.

      DISCUSSION

      ROS are produced by a variety of sources, mitochondrial oxidative phosphorylation, ionizing radiation exposures, cytokines, growth factors, metabolism of exogenous compounds, and pathological metabolic processes. These ROS are involved in many natural and pathological processes, including aging, cancer, diabetes mellitus, atherosclerosis, neurological degeneration, angiogenesis, and metastasis (
      • Shackelford R.E.
      • Kaufmann W.K.
      • Paules R.S.
      ). Metastasis requires several sequential steps as described earlier, and a rate-limiting step is degradation of matrix by active MMP-2 and MMP-9 (
      • Chang C.
      • Werb Z.
      ). Overproduction of the proenzyme was not sufficient for the acquisition of an invasive phenotype as only activated MMPs can degrade the matrix. However, there are few reports on specific mechanisms of MMPs activation and transcriptional regulation of MT1-MMP expression. Here we try to elucidate what kinds of ROS and how ROS regulate pro-MMPs activation and MT1-MMP expression. To our knowledge, this is the first described intercellular regulation of MT1-MMP by ROS.
      PMS and paraquat have been used as superoxide anion-producing agents (
      • Clement M.V.
      • Stamenkovic I.
      ,
      • Copin J.C.
      • Gasche Y., Li, Y.
      • Chan P.H.
      ,
      • Gardner P.R.
      • Raineri I.
      • Epstein L.B.
      • White C.W.
      ,
      • Marsh J.P.
      • Mossman B.T.
      ). PMS increased pro-MMP-2 activation (Fig. 2), cell motility, and the invasion of cancer cells (Fig. 10), but treatment with H2O2, peroxynitrite, and SNP (nitric oxide production) did not have an influence on the activation of MMPs and the tumor invasion. The produced superoxide anion turns into H2O2 by superoxide dismutase and is further catalyzed to H2O by catalase and glutathione peroxidase or hydroxyl radical by metal ions, such as iron. As shown in Fig. 2, H2O2 is responsible for pro-MMP-2 activation, raising an important question. Why did direct H2O2 treatment and PMS-induced H2O2 show different results? As shown in Fig.3, PMS increased intracellular and extracellular superoxide and H2O2 even 48 h after treatment, but one time treatment with H2O2 did not sustain intracellular H2O2 over 2 h, which was assayed by a flow cytometric analysis using DCFH-DA (data not shown).
      Regulation of MMP-9 expression is well established, but mechanistic processes of MMP-2 and MT1-MMP expressions and activation of pro-MMP-2 by ROS are not well understood. MMP-9 expression is regulated by c-Jun NH2-terminal kinase, p38, extracellular signal-regulated kinase, protein kinase C, and Ras pathway, dependent on cell types (
      • Westermarck J.
      • Kahari V.M.
      ). It has been shown that noncytotoxic H2O2 acts as an intracellular messenger and activates c-Jun NH2-terminal kinase, p38, extracellular signal-regulated kinase, cAMP-dependent protein kinase, protein kinase C, Ras, tyrosine kinases, and various other kinds of signal molecules (
      • Rhee S.G.
      • Bae Y.S.
      • Lee S.R.
      • Kwon J.
      ,
      • Guyton K.Z.
      • Liu Y.
      • Gorospe M., Xu, Q.
      • Holbrook N.J.
      ). To find the exact mechanism for H2O2-induced pro-MMP-2 activation, various kinds of inhibitors were treated. In contrast to MMP-9 expression, pro-MMP-2 activation by PMS was not affected by mitogen-activated protein kinases, cAMP-dependent protein kinase, protein kinase C, protein kinase G, Ras, and phospholipase A2 (Fig.5A). However, genistein, a tyrosine kinase inhibitor, inhibited pro-MMP-2 activation (Fig. 6A) through MT1-MMP down-regulation (Fig. 6B), and specifically PDGF and VEGF receptors, receptor tyrosine kinases, were involved in PMS action about 75–85 and 20–30%, respectively (Fig. 7A). In addition, a protein tyrosine phosphatase inhibitor plus PMS increased more pro-MMP-2 activation (Fig. 6A). Furthermore, it was found that PI3-kinase (Fig. 5) and NF-κB activations (Fig. 8) are also involved in a signal pathway of pro-MMP-2 activation through induction of MT1-MMP expression. It is well established that growth factors induce PI3-K activation, and in turn NF-κB activation (
      • Karin M.
      • Ben-Neriah Y.
      ), especially PDGF activates NF-κB through Ras and PI3-K (
      • Romashkova J.A.
      • Makarov S.S.
      ,
      • Marumo T.
      • Schini-Kerth V.B.
      • Fisslthaler B.
      • Busse R.
      ). In our studies, the Ras inhibitor did not reduce pro-MMP-2 activation (Fig. 5A). It is shown that HT1080 cells express PDGF and the PDGF receptor (
      • Gupta S.
      • Stuffrein S.
      • Plattner R.
      • Tencati M.
      • Gray C.
      • Whang Y.E.
      • Stanbridge E.J.
      ). Therefore, these results demonstrate that the PDGF/PI3-K/NF-κB pathway plays a key role in pro-MMP-2 activation through MT1-MMP induction by the sustained production of H2O2. The tyrosine kinase pathway was also critical for MMP-2 expression (Fig. 6B) as well as pro-MMP-2 activation.
      There are several reports on relationships between ROS, protein tyrosine kinase, and NF-κB. It has been suggested that the stimulatory effect of ROS on tyrosine phosphorylation is due to the kinase activation in addition to phosphatase inhibition (
      • Schieven G.L.
      • Kirihara J.M.
      • Myers D.E.
      • Ledbetter J.A.
      • Uckun F.M.
      ), and ROS also increase expression of the growth factors and the phosphorylation of growth factor receptors, types of receptor tyrosine kinases (
      • Rhee S.G.
      • Bae Y.S.
      • Lee S.R.
      • Kwon J.
      ). The activation of receptor tyrosine kinases, such as VEGF receptor and PDGF receptor, increases H2O2 via PI3-K has been reported previously (
      • Colavitti R.
      • Pani G.
      • Bedogni B.
      • Anzevino R.
      • Borrello S.
      • Waltenberger J.
      • Galeotti T.
      ,
      • Sundaresan M., Yu, Z.X.
      • Ferrans V.J.
      • Irani K.
      • Finkel T.
      ,
      • Bae Y.S.
      • Sung J.Y.
      • Kim O.S.
      • Kim Y.J.
      • Hur K.C.
      • Kazlauskas A.
      • Rhee S.G.
      ). Therefore, it can be explained that the sustained production of H2O2 by PMS activates PDGF, VEGF, PI3-K, and the NF-κB pathways. In turn PDGF/PI3-K and VEGF/PI3-K pathways increase H2O2, which is a positive feedback loop, consisting of H2O2, PDGF, VEGF, and PI3-K.
      Pro-MMP-2 activation by ROS may depend on cell types. The sustained production of H2O2 induced pro-MMP-2 activation in HT1080 cells and human endothelial cells, but T98G and NIH3T3 cells did not show any effect with the same treatment (Fig. 9A). This indicates that different cells react differently to the same stimulator. Cells having a large amount of MT1-MMP, even weak stimulations, can lead to pro-MMP-2 activation. If cells have a small amount of MT1-MMP such as NIH3T3 and T98G, even strong stimulators cannot activate pro-MMP-2, even though the level of MMP-2 expression is high, as in T98G (Fig. 9B). This implies a threshold of MT1-MMP level for MMP-2 activation. MT1-MMP is overexpressed in certain types of malignant tumor cells (
      • Yamamoto M.
      • Mohanam S.
      • Sawaya R.
      • Fuller G.N.
      • Seiki M.
      • Sato H.
      • Gokaslan Z.L.
      • Liotta L.A.
      • Nicolson G.L.
      • Rao J.S.
      ). Therefore, these cells can readily achieve the MT1-MMP threshold level and activate pro-MMP-2 and further promote metastasis and angiogenesis. However, many cells do not have large amounts of MT1-MMP; therefore, a transient increase in tyrosine kinases activity does not increase MT1-MMP to the threshold level. Only sustained stimulation of tyrosine kinases increases the potential of threshold level of MT1-MMP. HT1080 cells produce a large amount of MT1-MMP even without stimulator (Fig. 9B). This can be explained by constitutively active Akt, downstream target of PI3-K, in HT1080 (
      • Yoon S.O.
      • Kim M.M.
      • Park S.J.
      • Kim D.
      • Chung J.
      • Chung A.S.
      ). Further studies were performed on the relationship between PI3-K pathway and MT1-MMP expression in various cells. MT1-MMP not only participates in the processing of pro-MMP-2 but also digests various ECM components in vitro, including collagen (
      • Ohuchi E.
      • Imai K.
      • Fujii Y.
      • Sato H.
      • Seiki M.
      • Okada Y.
      ), thereby profoundly stimulating tumor cell invasion. These data explain why ROS such as H2O2 accelerate metastasis and angiogenesis.
      Besides matrix degradation by active MMPs, the cell-cell adhesion, cell-matrix adhesion, and cell motility are closely associated with tumor cell invasion and metastasis (
      • Liotta L.A.
      • Steeg P.S.
      • Stetler-Stevenson W.G.
      ,
      • Genda T.
      • Sakamoto M.
      • Ichida T.
      • Asakura H.
      • Hirohashi S.
      ,
      • Kaczarek E.
      • Zapf S.
      • Bouterfa H.
      • Tonn J.C.
      • Westphal M.
      • Giese A.
      ). For cells to invade the matrix, intercellular adhesions are weakened and tumor cells separate from solid tumor tissue. Therefore, weakening of the cell-cell interaction accelerates tumor cell invasion. In addition, cellular survival and invasion are promoted by cell-matrix interaction via integrins. PMS reduced cell-cell interaction (Fig. 10A) and increased cell motility (Fig. 10, C and D) but did not affect cell-collagen interaction (Fig. 10B). It has been shown that superoxide anion treatment enhances cell motility (
      • Muramatsu H.
      • Kogawa K.
      • Tanaka M.
      • Okumura K.
      • Nishihori Y.
      • Koike K.
      • Kuga T.
      • Niitsu Y.
      ), but our studies showed that sustained production of H2O2 by PMS is responsible for the increased motility and invasion, but not superoxide anion, because DDC treatment in the presence of PMS prevented these phenomena (Fig. 10, C–E).
      This study may explain the destructive role of chronic inflammation on tissue. Inflammatory reactions, particularly chronic ones, can be a significant source of oxidative stress. Leukocytes such as activated macrophages and neutrophils release a number of ROS including H2O2 and superoxide anion that can damage the nearby cells, and furthermore, these ROS have the potential to change normal cells to tumor cells. It has been estimated that approximately one-third of the world's cancers are due to the effects of chronic inflammation (
      • Klein G.
      ). In addition, inflammation is found during matrix remodeling in many clinical situations, including wound healing and tumor invasion, thereby increasing tumor cell metastasis, which is still not well understood. Tumor cells produce large amounts of ROS (
      • Szatrowski T.P.
      • Nathan C.F.
      ), and sublethal amounts of superoxide anion protect cells from apoptosis (
      • Clement M.V.
      • Stamenkovic I.
      ). During inflammation, NF-κB, which is known to be involved in cell survival, invasion, metastasis, and angiogenesis, is activated (
      • Janssen-Heininger Y.M.
      • Poynter M.E.
      • Baeuerle P.A.
      ). From this combined information, it can be proposed that the sustained production of H2O2 from chronic inflammation increases tumor cell resistance against the defense system of the body and invasion through 1) a decrease in cell-cell attachment, 2) an increase in matrix degradation by increasing the MT1-MMP expression and activation of pro-MMP-2, and 3) an increase in cell motility. In particular, the protein tyrosine kinase/PI3-K/NF-κB pathway may be most important for pro-MMP-2 activation through MT1-MMP induction by chronic inflammation-induced H2O2. Antioxidants such as N-acetylcysteine and protein tyrosine kinase inhibitors such as genistein can be good candidates for the application of anti-metastatic drugs.

      ACKNOWLEDGEMENT

      We thank Dr. V. Imbert (Faculte de Medecine, France) for the kind gift of the IκB-α vector.

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