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Hepatocyte Growth Factor/Scatter Factor Inhibits UVB-induced Apoptosis of Human Keratinocytes but Not of Keratinocyte-derived Cell Lines via the Phosphatidylinositol 3-Kinase/AKT Pathway*

Open AccessPublished:January 30, 2002DOI:https://doi.org/10.1074/jbc.M110687200
      Acute irrepairable UV-induced DNA damage leads to apoptosis of epidermal keratinocytes (KC) and the formation of sunburn cells, whereas less severely damaged cells survive but harbor the potential of tumor formation. Here we report that hepatocyte growth factor/scatter factor (HGF/SF) prevents UVB-induced apoptosis in primary KC cultured in vitro. When we analyzed the signaling pathways initiated by the HGF/SF receptor c-met, we found that the phosphatidylinositol (PI) 3-kinase and its downstream-element AKT and the mitogen-activated protein (MAP) kinase were activated. Inhibition of PI 3-kinase led to a complete abrogation of the anti-apoptotic effect of HGF/SF, whereas blockade of the MAP kinase pathway had no effect. In contrast to the observation with primary KC, HGF/SF could not enhance survival after UVB irradiation of HaCaT and A431 cell lines, despite the fact that in these cells the PI 3-kinase and MAP kinase pathways were also activated by HGF/SF. Cell cycle analysis of KC revealed a G2/M arrest after UVB irradiation and a complete loss of proliferating cells. Because HGF/SF in the skin is produced by dermal fibroblasts, our findings suggest that the HGF/SF-mediated rescue of KC from apoptosis represents an important paracrine loop by which UVB-damaged KC can be kept alive to maintain the epidermal barrier function but cannot further proliferate, thereby preventing the induction of epithelial skin tumors.
      HGF/SF
      The abbreviations used are: HGF/SF
      hepatocyte growth factor/scatter factor
      KC
      normal epidermal keratinocyte(s)
      PI
      phosphatidylinositol
      AKT
      protein kinase B
      MAP
      mitogen-activated protein
      KBM
      KC basic medium
      1The abbreviations used are: HGF/SF
      hepatocyte growth factor/scatter factor
      KC
      normal epidermal keratinocyte(s)
      PI
      phosphatidylinositol
      AKT
      protein kinase B
      MAP
      mitogen-activated protein
      KBM
      KC basic medium
      derived from mesenchymal cells is a multifunctional cytokine that has been shown to have a variety of effects on cells of different origin. It was first identified as a potent mitogen for hepatocytes (
      • Montesano R.
      • Matsumoto K.
      • Nakamura T.
      • Orci L.
      ,
      • Nakamura T.
      • Nishizawa T.
      • Hagiya M.
      • Seki T.
      • Shimonishi M.
      • Sugimura A.
      • Tashiro K.
      • Shimizu S.
      ), and more recently it was shown to promote cell motility and proliferation of KC, melanocytes, and kidney epithelial cells (for review see Ref.
      • Rubin J.S.
      • Bottaro D.P.
      • Aaronson S.A.
      ). Furthermore, HGF/SF is able to induce scattering of cells (
      • Stoker M.
      • Gherardi E.
      • Perryman M.
      • Gray J.
      ) and their invasion into extracellular matrix (
      • Giordano S.
      • Zhen Z.
      • Medico E.
      • Gaudino G.
      • Galimi F.
      • Comoglio P.M.
      ), thereby promoting tumor metastasis (
      • Jeffers M.
      • Rong S.
      • Vande W.G.
      ,
      • Weidner K.M.
      • Di C.S.
      • Sachs M.
      • Brinkmann V.
      • Behrens J.
      • Birchmeier W.
      ). Recently HGF/SF has been shown to promote or inhibit apoptosis depending on the cell type. For example, in the renal epithelial cell line HKC, HGF/SF acts as a survival factor after serum withdrawal (
      • Liu Y.
      • Sun A.M.
      • Dworkin L.D.
      ,
      • Yo Y.
      • Morishita R.
      • Nakamura S.
      • Tomita N.
      • Yamamoto K.
      • Moriguchi A.
      • Matsumoto K.
      • Nakamura T.
      • Higaki J.
      • Ogihara T.
      ); it inhibits hepatocyte apoptosis in Fas-induced fulminant hepatic failure in a mouse model (
      • Kosai K.
      • Matsumoto K.
      • Nagata S.
      • Tsujimoto Y.
      • Nakamura T.
      ) but is able to induce apoptosis of sarcoma 180 cells (
      • Arakaki N.
      • Kazi J.A.
      • Kazihara T.
      • Ohnishi T.
      • Daikuhara Y.
      ).
      The receptor for HGF/SF is a heterodimeric tyrosine kinase encoded by the c-met proto-oncogene, consisting of a 50-kDa extracellular α-subunit and a 145-kDa transmembrane β-subunit (
      • Bottaro D.P.
      • Rubin J.S.
      • Faletto D.L.
      • Chan A.M.
      • Kmiecik T.E.
      • Vande W.G.
      • Aaronson S.A.
      ). c-met signaling is mediated by autophosphorylation on Tyr1334 and Tyr1335 of the β-subunit, which leads to a strong up-regulation of its kinase activity (
      • Longati P.
      • Bardelli A.
      • Ponzetto C.
      • Naldini L.
      • Comoglio P.M.
      ). As a result, a multifunctional docking site for adaptor molecules on the C-terminal tail of the β-subunit becomes phosphorylated at the tyrosine residues on position Tyr1349 and Tyr1356. Their phosphorylation leads to interaction of c-met with several cytoplasmic signal transducers. This occurs either directly, such as with the PI 3-kinase, or indirectly via molecular adapters such as Grb2 (
      • Ponzetto C.
      • Zhen Z.
      • Audero E.
      • Maina F.
      • Bardelli A.
      • Basile M.L.
      • Giordano S.
      • Narsimhan R.
      • Comoglio P.
      ), Shc (
      • Pelicci G.
      • Giordano S.
      • Zhen Z.
      • Salcini A.E.
      • Lanfrancone L.
      • Bardelli A.
      • Panayotou G.
      • Waterfield M.D.
      • Ponzetto C.
      • Pelicci P.G.
      • Comoglio P.M.
      ), or Gab1 (
      • Weidner K.M.
      • Di C.S.
      • Sachs M.
      • Brinkmann V.
      • Behrens J.
      • Birchmeier W.
      ), activating the MAP kinase (
      • Ponzetto C.
      • Bardelli A.
      • Zhen Z.
      • Maina F.
      • Dalla Z.P.
      • Giordano S.
      • Graziani A.
      • Panayotou G.
      • Comoglio P.M.
      ) and the STAT-3 pathways (
      • Boccaccio C.
      • Ando M.
      • Tamagnone L.
      • Bardelli A.
      • Michieli P.
      • Battistini C.
      • Comoglio P.M.
      ). The MAP kinase pathway has been shown to be responsible for cell growth (
      • Ponzetto C.
      • Zhen Z.
      • Audero E.
      • Maina F.
      • Bardelli A.
      • Basile M.L.
      • Giordano S.
      • Narsimhan R.
      • Comoglio P.
      ), whereas the phosphorylation of STAT-3 and the resulting nuclear signaling is required for triggering differentiation for branching morphogenesis (
      • Boccaccio C.
      • Ando M.
      • Tamagnone L.
      • Bardelli A.
      • Michieli P.
      • Battistini C.
      • Comoglio P.M.
      ). The PI 3-kinase pathway is responsible for cell scattering by inducing the loss of intercellular junctions and cell migration (
      • Royal I.
      • Park M.
      ). This pathway has recently been shown to also be involved in the anti-apoptotic activity of HGF/SF in renal tubular epithelial cell line (
      • Liu Y.H.
      ), in hepatocytes (
      • Webster C.R.
      • Anwer M.S.
      ), and in NIH 3T3 fibroblasts (
      • Xiao G.H.
      • Jeffers M.
      • Bellacosa A.
      • Mitsuuchi Y.
      • Vande Woude G.F.
      • Testa J.R.
      ).
      For the skin, UV irradiation is the most important DNA damaging stimulus and represents the major risk factor for the development of epithelial skin tumors (
      • Kraemer K.H.
      ). Whereas mild UV-induced damage induces DNA repair, severe UV exposure leads to irrepairable DNA damage resulting in KC apoptosis and the formation of sunburn cells (
      • Brash D.E.
      • Ziegler A.
      • Jonason A.S.
      • Simon J.A.
      • Kunala S.
      • Leffell D.J.
      ,
      • Schwarz A.
      • Bhardwaj R.
      • Aragane Y.
      • Mahnke K.
      • Riemann H.
      • Metze D.
      • Luger T.A.
      • Schwarz T.
      ). It has been suggested that this UV-induced apoptosis contributes to the homeostasis of the epidermis and helps to prevent skin cancer by preferentially eliminating DNA-damaged KC (
      • Brash D.E.
      ). However, because a substantial loss of keratinocytes would result in a life-threatening damage of the skin barrier function, we are interested in mechanisms that counteract UV-induced KC apoptosis. In the present study we demonstrate that HGF/SF inhibits UV-induced apoptosis of KC and arrests them irreversibly in the G2/M phase of the cell cycle.

      DISCUSSION

      Apoptosis is the consequence of a genetically determined cell death program that can be initiated by a number of stimuli such as growth factor withdrawal, signaling through apoptotic receptors, or cell damaging stress (for review see Ref.
      • Rich T.
      • Watson C.J.
      • Wyllie A.
      ). Induction of apoptosis by DNA damaging agents plays a central role in the elimination of genetically altered cells, contributing to the inhibition of tumor development (
      • Brash D.E.
      • Ziegler A.
      • Jonason A.S.
      • Simon J.A.
      • Kunala S.
      • Leffell D.J.
      ). In the skin UV irradiation is the most relevant DNA damaging stimulus and represents the major risk factor for the development of epithelial skin tumors (
      • Kraemer K.H.
      ). Whereas mild UV-induced damage induces DNA repair, severe UV exposure leads to irrepairable DNA damage resulting in KC apoptosis and the formation of sunburn cells (
      • Brash D.E.
      • Ziegler A.
      • Jonason A.S.
      • Simon J.A.
      • Kunala S.
      • Leffell D.J.
      ,
      • Schwarz A.
      • Bhardwaj R.
      • Aragane Y.
      • Mahnke K.
      • Riemann H.
      • Metze D.
      • Luger T.A.
      • Schwarz T.
      ).
      In the present study, we demonstrate that UVB-induced apoptosis of human KC in primary culture is completely inhibited by HGF/SF in the absence of other growth factors. In contrast to primary KC, identical treatment had no effect on the survival of the two autonomously growing KC-derived cell lines HaCaT and A431. In our experiments, we identified the PI 3-kinase/AKT pathway as the one responsible for conferring UV resistance to KC, i.e. both wortmannin and LY294002 completely abolished the anti-apoptotic effect of HGF/SF. This part of our data complements recent data by others who showed that HGF/SF confers protection against apoptosis of a renal epithelial cell line (
      • Liu Y.H.
      ), of NIH 3T3 cells (
      • Xiao G.H.
      • Jeffers M.
      • Bellacosa A.
      • Mitsuuchi Y.
      • Vande Woude G.F.
      • Testa J.R.
      ), and of hepatocytes (
      • Webster C.R.
      • Anwer M.S.
      ) via the PI 3-kinase pathway. Blockade of the MAP kinase pathway by PD98059 had no effect on KC survival, which was surprising because activation of this pathway by insulin-like growth factor-1 has been shown to protect KC against UV-induced apoptosis (
      • Kuhn C.
      • Hurwitz S.A.
      • Kumar M.G.
      • Cotton J.
      • Spandau D.F.
      ).
      Our finding that HGF/SF, although protecting KC, could not prevent apoptosis of A431 and HaCaT cells was unexpected because Tang et al. (
      • Tang K.Q.
      • Nie D.T.
      • Cai Y.L.
      • Honn K.V.
      ) have recently reported that activating the PI 3-kinase pathway via β4 integrin protects A431 cells from apoptosis. Our data exclude the possibility that the lack of protection was due to an impaired PI 3-kinase signaling, because we demonstrated that like in primary KC, activation via c-met led to AKT phosphorylation in A431 and HaCaT cells. In the light of the data of Tang et al., namely that the PI 3-kinase pathway is functional in prevention of apoptosis in A431 cells, our results suggest that in these cells, either pathways downstream of AKT cannot be activated efficiently via c-met or its activation does not lead to protection from UV-mediated apoptosis. As to the first possibility, although we could demonstrate that the MAP kinase signaling and although the activation of AKT via c-met is intact in all three cell types analyzed, we cannot rule out at present that the signaling downstream of AKT is disturbed. Phosphorylation of AKT leads to the activation and inactivation of several factors that have been shown to be involved in the induction or prevention of apoptosis. For example GSK-3, a ubiquitously expressed serine/threonine protein kinase (
      • Pap M.
      • Cooper G.M.
      ); FKHR, a member of the Forkhead family of transcription factors (
      • Pap M.
      • Cooper G.M.
      ,
      • Rena G.
      • Guo S.
      • Cichy S.C.
      • Unterman T.G.
      • Cohen P.
      ); and Bad, an apoptotic member of the Bcl-2 family (
      • Datta S.R.
      • Dudek H.
      • Tao X.
      • Masters S.
      • Fu H.
      • Gotoh Y.
      • Greenberg M.E.
      ), are molecules that become phosphorylated by activated AKT. If any or a combination of these pathways is disturbed in the KC-derived cell lines, then no signal transduction would take place despite the presence of a functional receptor. Our finding that the amount of phosphorylated AKT was considerably lower in the cell lines than in KC suggests that in the cell lines activation of the downstream pathway might be less effective than in KC. As to the second possibility, it is tempting to speculate that different triggers of apoptosis, i.e. UV-induced DNA damage, as opposed to lack of membrane signaling via integrins might account for differing protection by HGF/SF in these cells. However, further studies will be necessary to test this hypothesis.
      Furthermore, with regard to the observed differences between primary cells and autonomously growing cell lines, different pathways of cell death signaling might be the cause for the distinct anti-apoptotic effects of HGF/SF. Both HaCaT and A431 cells contain mutations in the p53 gene, which plays a central role in UV-induced apoptosis (
      • Henseleit U.
      • Zhang J.
      • Wanner R.
      • Haase I.
      • Kolde G.
      • Rosenbach T.
      ,
      • Reiss M.
      • Brash D.E.
      • Munoz A.T.
      • Simon J.A.
      • Ziegler A.
      • Vellucci V.F.
      • Zhou Z.L.
      ). Therefore, it is highly probable that UV-induced DNA damage leads to apoptosis via p53-dependent and -independent pathways in primary cells and cell lines, respectively. That indeed DNA damage and not UV-induced membrane effects such as the clustering of CD95 (
      • Aragane Y.
      • Kulms D.
      • Metze D.
      • Wilkes G.
      • Poppelmann B.
      • Luger T.A.
      • Schwarz T.
      ) was the primary responsible apoptotic trigger in our experiments is strongly suggested by our finding that UV-induced apoptosis occurred after irradiation of cells at 25 °C as well as at 4 °C (data not shown). Irradiation at 4 °C blocks UVB-induced CD95 clustering but has no effect on UV-mediated DNA damage (
      • Aragane Y.
      • Kulms D.
      • Metze D.
      • Wilkes G.
      • Poppelmann B.
      • Luger T.A.
      • Schwarz T.
      ).
      As to the biological implications of our findings, it is important to keep in mind that in the skin dermal fibroblasts are a powerful source for HGF/SF (
      • Stoker M.
      • Perryman M.
      ). HGF/SF production is induced in these cells after stimulation with phorbol ester (
      • Gohda E.
      • Kataoka H.
      • Tsubouchi H.
      • Daikilara Y.
      • Yamamoto I.
      ), interleukin-1 (
      • Matsumoto K.
      • Okazaki H.
      • Nakamura T.
      ), and tumor necrosis factor-α (
      • Tamura M.
      • Arakaki N.
      • Tsubouchi H.
      • Takada H.
      • Daikuhara Y.
      ). Because production the latter two factors by KC is induced by UV irradiation (
      • Kupper T.S.
      • Chua A.O.
      • Flood P.
      • McGuire J.
      • Gubler U.
      ,
      • Kock A.
      • Schwarz T.
      • Kirnbauer R.
      • Urbanski A.
      • Perry P.
      • Ansel J.C.
      • Luger T.A.
      ), their secretion would result in the triggering of HGF/SF production by fibroblasts and the establishment of a paracrine loop between epidermal and dermal symbionts, allowing the survival of KC after UV injury.
      UV-induced apoptosis is thought to contribute to skin homeostasis by preferentially eliminating KC with irreparable DNA damage,i.e. potentially precancerous cells, and has been referred to as “cellular proofreading” (
      • Brash D.E.
      ), in analogy to proofreading and excision of incorrect base pairs during DNA synthesis. Indeed, mice that are deficient in p53 and therefore have a decreased capacity of DNA repair show a decreased tendency of sunburn cell formation and are more susceptible to the development of UV-induced tumors (
      • Hill L.L.
      • Ouhtit A.
      • Loughlin S.M.
      • Kripke M.L.
      • Ananthaswamy H.N.
      • Owen S.L.
      ). For this reason UV-induced KC apoptosis by itself cannot merely be regarded as a harmful event but is thought to help reduce or prevent skin carcinogenesis (
      • Brash D.E.
      ,
      • Hill L.L.
      • Ouhtit A.
      • Loughlin S.M.
      • Kripke M.L.
      • Ananthaswamy H.N.
      • Owen S.L.
      ). Protection of KC by the inhibition of apoptosis might therefore be a double-edged sword potentially favoring the survival of cells with DNA damage. A possibility to circumvent such a harmful scenario would be that HGF/SF-protected KC enter a postmitotic state. We could show in our experiments that KC protected by HGF/SF do not further proliferate in vitro. If this holds true in vivo, these cells would be removed from the replicating population, thereby reducing the risk of transformation while keeping them alive and thus maintaining the integrity of the skin barrier. With regard to the differences observed between cells in primary culture and cell lines bearing p53 mutations, it is tempting to speculate that HGF/SF might preferentially protect nontransformed KCin vivo while leaving transformed cells to be eliminated by UV irradiation, implying a possible beneficial effect of strong UV irradiation in the removal of precancerous epithelial skin lesions.

      Acknowledgments

      We thank H. Rossiter for critical reading of the manuscript.

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