PINCH-1 Regulates the ERK-Bim Pathway and Contributes to Apoptosis Resistance in Cancer Cells

Abstract

Resistance to apoptosis is a hallmark of cancer cells. We report here that PINCH-1, a cytoplasmic component of cell-extracellular matrix adhesions, is required for protection of multiple types of cancer cells from apoptosis. Furthermore, using HT-1080 fibrosarcoma cells as a model system, we have investigated the signaling pathway through which PINCH-1 contributes to apoptosis resistance. Loss of PINCH-1 markedly increases the level of Bim and promotes Bim translocation to mitochondria, resulting in activation of the intrinsic apoptosis pathway. Depletion of Bim completely blocked apoptosis induced by the loss of PINCH-1. Thus, PINCH-1 contributes to apoptosis resistance through suppression of Bim. Mechanistically, PINCH-1 suppresses Bim not only transcriptionally but also post-transcriptionally. PINCH-1 promotes activating phosphorylation of Src family kinase and ERK1/2. Consistent with this, ERK1/2-mediated Ser69 phosphorylation of Bim, a key signal for turnover of Bim, is suppressed by the removal of PINCH-1. Our results demonstrate a strong dependence of multiple types of apoptosis-resistant cancer cells on PINCH-1 and provide new insights into the molecular mechanism by which cancer cells are protected from apoptosis. Resistance to apoptosis is a hallmark of cancer cells. We report here that PINCH-1, a cytoplasmic component of cell-extracellular matrix adhesions, is required for protection of multiple types of cancer cells from apoptosis. Furthermore, using HT-1080 fibrosarcoma cells as a model system, we have investigated the signaling pathway through which PINCH-1 contributes to apoptosis resistance. Loss of PINCH-1 markedly increases the level of Bim and promotes Bim translocation to mitochondria, resulting in activation of the intrinsic apoptosis pathway. Depletion of Bim completely blocked apoptosis induced by the loss of PINCH-1. Thus, PINCH-1 contributes to apoptosis resistance through suppression of Bim. Mechanistically, PINCH-1 suppresses Bim not only transcriptionally but also post-transcriptionally. PINCH-1 promotes activating phosphorylation of Src family kinase and ERK1/2. Consistent with this, ERK1/2-mediated Ser69 phosphorylation of Bim, a key signal for turnover of Bim, is suppressed by the removal of PINCH-1. Our results demonstrate a strong dependence of multiple types of apoptosis-resistant cancer cells on PINCH-1 and provide new insights into the molecular mechanism by which cancer cells are protected from apoptosis. Apoptosis is a fundamental cellular process that is essential for normal development in embryo and tissue homeostasis in adult. Resistance to apoptosis is crucial for pathogenesis and progression of many common human diseases, including cancer (1Hanahan D. Weinberg R.A. Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (22623) Google Scholar). It has been shown, for example, that the metastatic potential of human cancer cells is strictly linked to increased resistance to apoptosis (2Glinsky G.V. Glinsky V.V. Ivanova A.B. Hueser C.J. Cancer Lett. 1997; 115: 185-193Crossref PubMed Scopus (135) Google Scholar). Experimental modulation of key antiapoptotic or proapoptotic factors alters metastatic efficiency (reviewed in Ref. 3Mehlen P. Puisieux A. Nat. Rev. Cancer. 2006; 6: 449-458Crossref PubMed Scopus (1405) Google Scholar). Thus, apoptosis provides a major barrier to metastasis (1Hanahan D. Weinberg R.A. Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (22623) Google Scholar, 3Mehlen P. Puisieux A. Nat. Rev. Cancer. 2006; 6: 449-458Crossref PubMed Scopus (1405) Google Scholar). Overcoming resistance of cancer cells to apoptosis, therefore, represents both a challenge and an exciting opportunity in cancer biology and therapy. To achieve this goal, it is essential to identify proteins that protect cancer cells from apoptosis and determine signaling pathways through which they protect cancer cells from apoptosis. Studies over the past 2 decades suggest that apoptosis is mediated primarily by two distinct signaling pathways, namely the extrinsic (or the death receptor) and the intrinsic (or the mitochondrial) pathways (reviewed in Refs. 4Strasser A. O'Connor L. Dixit V.M. Annu. Rev. Biochem. 2000; 69: 217-245Crossref PubMed Scopus (1387) Google Scholar, 5Adams J.M. Genes Dev. 2003; 17: 2481-2495Crossref PubMed Scopus (680) Google Scholar, 6Danial N.N. Korsmeyer S.J. Cell. 2004; 116: 205Abstract Full Text Full Text PDF PubMed Scopus (4059) Google Scholar). The extrinsic pathway is mediated by the FAS receptor (CD95) or members of the tumor necrosis factor receptor superfamily. The intrinsic pathway, on the other hand, involves multiple Bcl-2 family proteins (e.g. proapoptotic proteins, such as Bim and Bax, and prosurvival proteins, such as Bcl-2) (7Huang D.C.S. Strasser A. Cell. 2000; 103: 839-842Abstract Full Text Full Text PDF PubMed Scopus (902) Google Scholar, 8Puthalakath H. Strasser A. Cell Death Differ. 2002; 9: 505-512Crossref PubMed Scopus (631) Google Scholar, 9Green D.R. Kroemer G. Science. 2004; 305: 626-629Crossref PubMed Scopus (2830) Google Scholar), which impinge on mitochondrial integrity. The two apoptosis pathways converge on common “executioner” caspases (e.g. caspase-3) that are responsible for execution of apoptosis (10Degterev A. Boyce M. Yuan J. Oncogene. 2003; 22: 8543-8567Crossref PubMed Scopus (986) Google Scholar). Although the extrinsic and intrinsic apoptosis pathways have been well described, how cancer cells evade the activation of the apoptosis pathways remains elusive. The activation of the apoptosis pathways is controlled at least in part by integrin-mediated cell-extracellular matrix (ECM) 2The abbreviations used are: ECMextracellular matrixERKextracellular signal-regulated kinaseFAfocal adhesionAbantibodySFKSrc family kinase SFKsiRNAsmall interfering RNA. adhesion (reviewed in Refs. 11Frisch S.M. Screaton R.A. Curr. Opin. Cell Biol. 2001; 13: 555-562Crossref PubMed Scopus (1180) Google Scholar, 12Martin S.S. Vuori K. Biochim. Biophys. Acta. 2004; 1692: 145-157Crossref PubMed Scopus (83) Google Scholar, 13Reddig P.J. Juliano R.L. Cancer Metastasis Rev. 2005; 24: 425-439Crossref PubMed Scopus (354) Google Scholar, 14Hannigan G. Troussard A. Dedhar S. Nat. Rev. Cancer. 2005; 5: 51-63Crossref PubMed Scopus (509) Google Scholar). Thus, components of the integrin signaling pathway are attractive targets for therapeutic control of tumor growth and metastasis. At the molecular level, cell-ECM adhesion is mediated by a complex protein network consisting of integrins and proteins that are directly or indirectly associated with integrins (15Schwartz M.A. Schaller M.D. Ginsberg M.H. Annu. Rev. Cell Dev. Biol. 1995; 11: 549-599Crossref PubMed Scopus (1474) Google Scholar, 16Dedhar S. Hannigan G.E. Curr. Opin. Cell Biol. 1996; 8: 657-669Crossref PubMed Scopus (347) Google Scholar, 17Howe A. Aplin A.E. Alahari S.K. Juliano R.L. Curr. Opin. Cell Biol. 1998; 10: 220-231Crossref PubMed Scopus (587) Google Scholar, 18Aplin A.E. Howe A.K. Juliano R.L. Curr. Opin. Cell Biol. 1999; 11: 737-744Crossref PubMed Scopus (299) Google Scholar, 19Geiger B. Bershadsky A. Pankov R. Yamada K.M. Nat. Rev. Mol. Cell. Biol. 2001; 2: 793-805Crossref PubMed Scopus (1857) Google Scholar, 20Hynes R.O. Cell. 2002; 110: 673-687Abstract Full Text Full Text PDF PubMed Scopus (6951) Google Scholar, 21Miranti C.K. Brugge J.S. Nat. 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Although the role of PINCH-1 and Mig-2 in and cytoskeletal has been well their in apoptosis to of suggest that PINCH-1 in the suppression of apoptosis. of PINCH-1 from human cells promotes apoptosis Chen K. Shi X. Wu C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). an of cells in PINCH-1 S. R. F. M. A. O. R. J. Cell 2005; PubMed Scopus Google Scholar). apoptosis in PINCH-1 X. Li X. Y. M. J. Chen J. Mol. Cell. Biol. 2005; PubMed Scopus Google Scholar). of PINCH-1 in embryonic which many with metastatic cancer apoptosis X. Y. J. H. M. S. A. S. Chen J. 2007; 100: PubMed Scopus Google Scholar). of apoptosis, however, not in X. Li X. Y. M. J. Chen J. Mol. Cell. Biol. 2005; PubMed Scopus Google Scholar). an that PINCH-1 in protection of types of cells (e.g. cancer cells and cells that a from apoptosis. The role of Mig-2 in apoptosis not been matrix signal-regulated kinase focal adhesion Src family kinase interfering RNA. The on the role of PINCH-1 in protection of cancer cells from apoptosis. The of this are to protection apoptosis on PINCH-1 at to determine PINCH-1 contributes to apoptosis resistance in multiple types of human cancer and to identify the pathway that the of PINCH-1 in We report here the and HT-1080 fibrosarcoma and and cells from cells from Dedhar Cancer cells from of cancer cells from C. Bax, or cells F. A. C. S. J.M. B. Science. 1998; 282: PubMed Scopus Google Scholar, L. J. B. Science. 2000; PubMed Scopus Google Scholar, J. B. L. S. A. 2003; 100: PubMed Scopus Google Scholar, M. J. C. A. B. C. L. S. A. 2004; PubMed Scopus Google Scholar). and Y. Wu S. Shi X. Chen K. Wu C. Cell. 2003; 113: 37-47Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar, F. Y. Wu C. J. Cell 1999; PubMed Google Scholar, Y. Chen K. Tu Y. A. Y. Qin J. Wu C. J. Cell 2002; 115: PubMed Scopus Google Scholar). from and from Bim, in human and from Cell in human from and with from from from from and from from from Mig-2 and control Y. Wu S. Shi X. Chen K. Wu C. Cell. 2003; 113: 37-47Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar, Chen K. Shi X. Wu C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, Fukuda Li Y. X. Qin J. Wu C. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). from with or the control using the cells with an a PINCH-1 that is to the PINCH-1 Fukuda Li Y. X. Qin J. Wu C. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google or a PINCH-1 as a the cells with PINCH-1 2 with HT-1080 cells with PINCH-1 and control as the cells with 2 and for an The cells and by cells on at the cells with in with in and with and the with and in as in and with PINCH-1 or control as apoptosis using a the in The from cells with that of the control cells to using the from with the for The of Bim in PINCH-1 and control cells by using the The used and The in using the and using as a using the and the by from a human using and as and into the HT-1080 cells with the using of induced of apoptosis not To the in cells with PINCH-1 or control RNA. by PINCH-1 as we Y. Chen K. Tu Y. Wu C. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). the with with of of The and the proteins by of and and as J. S. Li X. Y. M. Wu M. Mol. Cell. Biol. 2005; PubMed Scopus Google Scholar). cells in and The through a and at for at to The at for at The and and by with for of mitochondrial and PINCH-1 and Mig-2 for into at that are by as which is for of integrin-mediated including cell-ECM adhesion, and B. Annu. Rev. Cell Dev. Biol. 2003; 19: PubMed Scopus Google Scholar). To determine protection apoptosis on of PINCH-1, we to a through which we but not the level of PINCH-1. this we a and cytoplasmic component of is required for of PINCH-1. HT-1080 fibrosarcoma which PINCH-1 and Mig-2 and with a and a that HT-1080 cells in which PINCH-1 and Mig-2 of the cells with an that targets Mig-2 the level of Mig-2 but not that of PINCH-1 protein by the with an and the of a normal level of PINCH-1 of PINCH-1 in Mig-2 cells with results suggest that Mig-2 is required for of PINCH-1, it is not required for the and of the cellular level of PINCH-1. We the PINCH-1 is required for of To this, we the cells with a PINCH-1 which we targets the PINCH-1 Chen K. Shi X. Wu C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). with the PINCH-1 markedly the level of PINCH-1 2 with a control by the with an and level of Mig-2 in both the cells and the control cells and that loss of PINCH-1 not the level of that the of Mig-2 and well in PINCH-1 cells with Thus, of PINCH-1 also of results suggest that PINCH-1 and Mig-2 are for their Loss of protein of the other PINCH-1, but for of HT-1080 from is required for the of cells Chen K. Shi X. Wu C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, Fukuda Li Y. X. Qin J. Wu C. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). It not however, PINCH-1 a role in protection of other cancer cells apoptosis. To to this, we apoptosis in to of PINCH-1 in HT-1080 cells. Depletion of PINCH-1 from HT-1080 cells markedly increased apoptosis of which of PINCH-1 not apoptosis results suggest that PINCH-1 is required for protection of HT-1080 cells apoptosis, and it through a mechanism that is of Mig-2 of of PINCH-1 for of of Cancer from the role of PINCH-1 in the of other types of cancer we PINCH-1 from human and and cells. and HT-1080 cells used as of the cells with PINCH-1 PINCH-1 in types that and and and Depletion of PINCH-1 markedly increased apoptosis in HT-1080 and cells as cells of apoptosis, however, in and cells as cells results suggest that PINCH-1 is required for protection of many types of cancer cells from apoptosis, it is in cancer and cells. of Apoptosis to determine the signaling in of apoptosis. in Bax, and are proteins in the of cancer cells in to Thus, we they are of in which the of of the proteins Bax, or F. A. C. S. J.M. B. Science. 1998; 282: PubMed Scopus Google Scholar, L. J. B. Science. 2000; PubMed Scopus Google Scholar, J. B. L. S. A. 2003; 100: PubMed Scopus Google Scholar, M. J. C. A. B. C. L. S. A. 2004; PubMed Scopus Google Scholar), used in cells that Bax, or and cells as a with PINCH-1 or a control RNA. Depletion of PINCH-1 in the PINCH-1 and and and but not the control and and and or the cells and and and by of PINCH-1 markedly increased in cells Loss of the of by a role of in this The of apoptosis also in the of of apoptosis in the of or results suggest that and to a but not or are in of apoptosis. PINCH-1 Bim but that the of apoptosis is on to the level of is in to loss of PINCH-1. the and control cells with an that the level of not in to loss of PINCH-1 and To this, we the of PINCH-1 on the level of in human cancer including both the and cells and and cells. of the level in to loss of PINCH-1 in of the cells that and Thus, a role in of apoptosis, it is not a of PINCH-1 We to identify the signaling that is by PINCH-1. is in PINCH-1 of apoptosis, we that this signaling of proteins, including Bim, and are known to of role of by and Bcl-2 not in and and and and in the or of PINCH-1. other the level of Bcl-2 not (e.g. in and or (e.g. in and in to loss of PINCH-1 and loss of PINCH-1 increased the Bim level in many (e.g. and not (e.g. and types of cancer cells is on PINCH-1 and of the Bim level in cells and is of PINCH-1 on we that in at least types of cancer Bim as a key signaling in to loss of PINCH-1. Bim as a in of to this HT-1080 in which the Bim level markedly increased in to loss of PINCH-1 and used as a model Our that Bim as a key signaling of PINCH-1 has loss of which alters of PINCH-1 but not apoptosis, not the Bim Consistent with this, that the Bim level in the Mig-2 cells that in the PINCH-1 cells not The of is that of PINCH-1 in the which suppresses apoptosis induced by the loss of PINCH-1 Fukuda Li Y. X. Qin J. Wu C. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), the of the Bim We this of PINCH-1 in the PINCH-1 cells the of Bim induced by the loss of PINCH-1 control of PINCH-1 also suppressed the of apoptosis induced by the loss of PINCH-1 The and the is that apoptosis induced by the loss of PINCH-1 blocked by of Bim. To this, we Bim in HT-1080 cells by of PINCH-1 increased the level of Bim and Depletion of Bim and completely blocked the of induced by the PINCH-1 To this, we PINCH-1 Bim or both PINCH-1 and Bim and from cells. of Bim completely blocked the of induced by the loss of PINCH-1 results provide strong for a role of Bim in of apoptosis. PINCH-1 Bim and we investigated how PINCH-1 the Bim that the Bim level increased in to loss of PINCH-1 that PINCH-1 suppresses Bim at least in at the of Bim is a major mechanism for cancer apoptosis induced by of HT-1080 cells with of PINCH-1 increased the level of Bim 2 and of PINCH-1 from cells in a of the Bim level with 2 or results suggest that PINCH-1 Bim not only transcriptionally but also post-transcriptionally. To this, we the cells with a that is controlled a of the with the PINCH-1 and the other with a control RNA. Depletion of PINCH-1 in the PINCH-1 but not the control by the level of in the cells that in the control cells and Thus, with a role of PINCH-1 in of Bim, loss of PINCH-1 increases not only the of Bim but also the level of Bim protein the level of Bim HT-1080 cells the control of the with the control or the PINCH-1 The by with and and from and control cells with The by with and of the PINCH-1 and control cells by with and and PINCH-1 and Ser69 of phosphorylation of at Ser69 is an signal for Bim turnover (reviewed in Ref. R. K. S.J. Cell Death Differ. 2005; 12: PubMed Scopus Google Scholar). We Ser69 phosphorylation is in to loss of PINCH-1. To this, we from PINCH-1 and control Consistent with the of a of from PINCH-1 cells 2 with the of the of Ser69 not increased and that loss of PINCH-1 the efficiency of phosphorylation of at of at Ser69 is by (reviewed in Ref. R. K. S.J. Cell Death Differ. 2005; 12: PubMed Scopus Google Scholar). The that loss of PINCH-1 the efficiency of Ser69 phosphorylation to of PINCH-1 Although the of proteins and the of that at the which is essential for in to loss of PINCH-1 by the with It has been well that an role in of R. Y. C.J. J. 1995; PubMed Scopus Google Scholar, Curr. Opin. Cell Biol. 1995; PubMed Scopus Google Scholar). loss of PINCH-1 of in human at the activation which is known to crucial for The level of not in to loss of PINCH-1 by the with an Thus, with of Ser69 phosphorylation of of PINCH-1 the activating phosphorylation of and ERK1/2. Loss of PINCH-1 Bim to and are the of apoptosis. To the mechanism PINCH-1 apoptosis, we mitochondrial and from the cells. a of mitochondria, in the mitochondrial and but not the and the with an as in the and but not the mitochondrial and that the mitochondrial and the level of mitochondrial Bim and but not that of Bim and markedly increased in cells. results suggest that loss of PINCH-1 not only increases the cellular level of Bim but also promotes Bim translocation to the to the of mitochondrial Bim level, loss of PINCH-1 the level of mitochondrial Bcl-2 and Depletion of Bim the of the Bcl-2 by the Loss of Bim the of PINCH-1 on To this, we suppressed the of Bim in PINCH-1 cells. of PINCH-1 in HT-1080 cells increased the level of mitochondrial Bim and the level of mitochondrial Bcl-2 of Bim and the of the mitochondrial Bcl-2 level induced by the loss of PINCH-1. results suggest that PINCH-1 the level of mitochondrial Bcl-2 through Bim, a role of Bim in protection apoptosis in cells. Cancer in metastatic cancer are to apoptosis induced by in the which to in metastasis. of proteins and signaling pathways that apoptosis resistance is an in cancer biology and therapy. We that of PINCH-1 apoptosis in cells Chen K. Shi X. Wu C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The results in this demonstrate that PINCH-1 is also required for protection of many other types of cancer including HT-1080 fibrosarcoma and and cancer from apoptosis. PINCH-1 is not required for the of cells and cells. on we that PINCH-1 as a key apoptosis in multiple types of cancer in cancer cells. results suggest a model in which PINCH-1 is in suppression of apoptosis in cancer cells. of PINCH-1 cancer cells to apoptosis resulting in a of apoptosis. Our on the apoptosis signaling pathway by the loss of PINCH-1 strong to this We have that the level of Bim is increased in to loss of PINCH-1 in types of cancer cells. Furthermore, of Bim completely the of apoptosis induced by the loss of PINCH-1. Thus, Bim to as a key in PINCH-1 of apoptosis How PINCH-1 regulate the Bim apoptosis The results in this suggest that PINCH-1 Bim at multiple loss of PINCH-1 increases the level of Bim, that PINCH-1 suppresses Bim at least in at the PINCH-1 the Bim level the level of controlled by a also increased in to of PINCH-1. loss of PINCH-1 increases the Bim level in the mitochondrial but not that of the that PINCH-1 also a role in of mitochondrial translocation of Bim. The that PINCH-1 Bim not only transcriptionally but also is with in which we that loss of PINCH-1 activation Chen K. Shi X. Wu C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). through phosphorylation of factor A. A. P. J. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, L. P.J. Curr. Biol. 2000; 10: Full Text Full Text PDF PubMed Scopus Google Scholar). 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A. 2004; PubMed Scopus Google Scholar), is in the of PINCH-1 and ERK1/2-mediated Ser69 phosphorylation of is a key signal for turnover R. K. S.J. Cell Death Differ. 2005; 12: PubMed Scopus Google and activation K. K. R. K. S.J. J. 2007; PubMed Scopus Google and of Bim apoptosis induced by the loss of PINCH-1 results suggest that the pathway represents a key pathway through which PINCH-1 apoptosis. the results from this and suggest that PINCH-1 in protection apoptosis through at least two it activation and the targets of (e.g. and it promotes activation and Ser69 phosphorylation and of How PINCH-1 regulate We have that PINCH-1 promotes activating phosphorylation of which is known to an role in of the pathway R. Y. C.J. J. 1995; PubMed Scopus Google Scholar, Curr. Opin. Cell Biol. 1995; PubMed Scopus Google Scholar). by with integrin (e.g. cytoplasmic or integrin proteins (e.g. focal adhesion (reviewed in Refs. S.J. Trends Cell Biol. 2005; 15: Full Text Full Text PDF PubMed Scopus Google Scholar, Biol. 1997; PubMed Scopus Google Scholar, J.T. J. Cell 2003; 116: PubMed Scopus Google Scholar, Schaller M.D. Oncogene. 2004; PubMed Scopus Google Scholar, S.K. Curr. Opin. Cell Biol. 2006; PubMed Scopus Google Scholar). Thus, it is that PINCH-1 in activation through of signaling mediated by integrins or are required to this the in this demonstrate a strong dependence of types of cancer cells on PINCH-1. Furthermore, new on the molecular mechanism by which the cancer cells are protected from apoptosis. We that PINCH-1 in the activating phosphorylation of and which are known to in of PINCH-1 from cancer cells and activation and promotes Bim resulting in activation of a apoptosis pathway. PINCH-1, therefore, to cancer cells and tumor growth and metastatic We and C. for the of cells. with