Proteomic Analysis Reveals a Role for Bcl2-associated Athanogene 3 and Major Vault Protein in Resistance to Apoptosis in Senescent Cells by Regulating ERK1/2 Activation

Senescence is a prominent solid tumor response to therapy in which cells avoid apoptosis and instead enter into prolonged cell cycle arrest. We applied a quantitative proteomics screen to identify signals that lead to therapy-induced senescence and discovered that Bcl2-associated athanogene 3 (Bag3) is up-regulated after adriamycin treatment in MCF7 cells. Bag3 is a member of the BAG family of co-chaperones that interacts with Hsp70. Bag3 also regulates major cell-signaling pathways. Mass spectrometry analysis of the Bag3 Complex revealed a novel interaction between Bag3 and Major Vault Protein (MVP). Silencing of Bag3 or MVP shifts the cellular response to adriamycin to favor apoptosis. We demonstrate that Bag3 and MVP contribute to apoptosis resistance in therapy-induced senescence by increasing the level of activation of extracellular signal-regulated kinase1/2 (ERK1/2). Silencing of either Bag3 or MVP decreased ERK1/2 activation and promoted apoptosis in adriamycin-treated cells. An increase in nuclear accumulation of MVP is observed during therapy-induced senescence and the shift in MVP subcellular localization is Bag3-dependent. We propose a model in which Bag3 binds to MVP and facilitates MVP accumulation in the nucleus, which sustains ERK1/2 activation. We confirmed that silencing of Bag3 or MVP shifts the response toward apoptosis and regulates ERK1/2 activation in a panel of diverse breast cancer cell lines. This study highlights Bag3-MVP as an important complex that regulates a potent prosurvival signaling pathway and contributes to chemotherapy resistance in breast cancer. Senescence is a prominent solid tumor response to therapy in which cells avoid apoptosis and instead enter into prolonged cell cycle arrest. We applied a quantitative proteomics screen to identify signals that lead to therapy-induced senescence and discovered that Bcl2-associated athanogene 3 (Bag3) is up-regulated after adriamycin treatment in MCF7 cells. Bag3 is a member of the BAG family of co-chaperones that interacts with Hsp70. Bag3 also regulates major cell-signaling pathways. Mass spectrometry analysis of the Bag3 Complex revealed a novel interaction between Bag3 and Major Vault Protein (MVP). Silencing of Bag3 or MVP shifts the cellular response to adriamycin to favor apoptosis. We demonstrate that Bag3 and MVP contribute to apoptosis resistance in therapy-induced senescence by increasing the level of activation of extracellular signal-regulated kinase1/2 (ERK1/2). Silencing of either Bag3 or MVP decreased ERK1/2 activation and promoted apoptosis in adriamycin-treated cells. An increase in nuclear accumulation of MVP is observed during therapy-induced senescence and the shift in MVP subcellular localization is Bag3-dependent. We propose a model in which Bag3 binds to MVP and facilitates MVP accumulation in the nucleus, which sustains ERK1/2 activation. We confirmed that silencing of Bag3 or MVP shifts the response toward apoptosis and regulates ERK1/2 activation in a panel of diverse breast cancer cell lines. This study highlights Bag3-MVP as an important complex that regulates a potent prosurvival signaling pathway and contributes to chemotherapy resistance in breast cancer. Cellular senescence plays an important role in determining the response of tumors to cancer therapy (1.Schmitt C.A. Cellular senescence and cancer treatment.Biochim. Biophys. Acta. 2007; 1775: 5-20PubMed Google Scholar). Senescence is regulated by the p53 and p16-pRB tumor suppressor pathways and characterized by irreversible cell cycle arrest and expression of the lysosomal protein, senescence associated beta galactosidase (SA-β-gal) 1The abbreviations used are:SA-β-galSenescence-associated beta-galactosidaseBag3Bcl2-associated athanogene 3TISTherapy induced senescenceMVPMajor Vault ProteinHSPHeat shock proteinPARP4Poly (ADP-ribose) polymerase family, member 4TEP1Telomerase associated protein 1ERKExtracellular signal-regulated kinaseJNKJun Kinase. 1The abbreviations used are:SA-β-galSenescence-associated beta-galactosidaseBag3Bcl2-associated athanogene 3TISTherapy induced senescenceMVPMajor Vault ProteinHSPHeat shock proteinPARP4Poly (ADP-ribose) polymerase family, member 4TEP1Telomerase associated protein 1ERKExtracellular signal-regulated kinaseJNKJun Kinase.. Additional characteristics of senescent cells include the presence of senescence-associated heterochromatic foci, and a senescence associated secretory phenotype (SASP) (2.Campisi J. d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells.Nat. Rev. Mol. Cell Biol. 2007; 8: 729-740Crossref PubMed Scopus (2979) Google Scholar). Because of the SASP of senescent cells, therapy-induced senescence (TIS) may be harmful in cancer and the quantitative elimination of senescent cells could prove to be therapeutically beneficial. A recent study demonstrated that pharmacologically targeting the metabolic pathways of TIS in vivo prompted tumor regression and improved treatment outcomes (3.Dorr J.R. Yu Y. Milanovic M. Beuster G. Zasada C. Dabritz J.H. Lisec J. Lenze D. Gerhardt A. Schleicher K. Kratzat S. Purfurst B. Walenta S. Mueller-Klieser W. Graler M. Hummel M. Keller U. Buck A.K. Dorken B. Willmitzer L. Reimann M. Kempa S. Lee S. Schmitt C.A. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy.Nature. 2013; 501: 421-425Crossref PubMed Scopus (350) Google Scholar). Senescence-associated beta-galactosidase Bcl2-associated athanogene 3 Therapy induced senescence Major Vault Protein Heat shock protein Poly (ADP-ribose) polymerase family, member 4 Telomerase associated protein 1 Extracellular signal-regulated kinase Jun Kinase. Senescence-associated beta-galactosidase Bcl2-associated athanogene 3 Therapy induced senescence Major Vault Protein Heat shock protein Poly (ADP-ribose) polymerase family, member 4 Telomerase associated protein 1 Extracellular signal-regulated kinase Jun Kinase. A characteristic of senescent cells is their ability to resist apoptosis although the responsible mechanism is poorly understood. Impairment of apoptosis in senescent cells is associated with a poor outcome in cancer (4.Jackson J.G. Pant V. Li Q. Chang L.L. Quintas-Cardama A. Garza D. Tavana O. Yang P. Manshouri T. Li Y. El-Naggar A.K. Lozano G. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer.Cancer Cell. 2012; 21: 793-806Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar). Manipulation of the apoptotic machinery may serve as a therapeutic means of eliminating senescent cells with harmful SASP. It has been proposed that in senescent cells, p53 may preferentially activate genes that arrest proliferation, rather than those that facilitate apoptosis. Alternatively, resistance to apoptosis may be caused by altered expression of proteins that inhibit, promote, or mediate apoptotic cell death, such as Bcl2. Bcl2 associated athanogene 3 (Bag3) is a member of the BAG family of chaperones that interacts with the ATPase domain of heat shock protein-70 (Hsp70). In addition to its BAG domain, Bag3 contains a WW domain and a proline-rich (PXXP) repeat, which mediates binding to partners other than Hsp70. Bag3 is expressed in response to cellular stress under the induction of HSF1 and is known to suppress apoptosis and regulate autophagy (5.Jacobs A.T. Marnett L.J. HSF1-mediated BAG3 expression attenuates apoptosis in 4-hydroxynonenal-treated colon cancer cells via stabilization of anti-apoptotic Bcl-2 proteins.J. Biol. Chem. 2009; 284: 9176-9183Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 6.Gamerdinger M. Hajieva P. Kaya A.M. Wolfrum U. Hartl F.U. Behl C. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3.EMBO J. 2009; 28: 889-901Crossref PubMed Scopus (409) Google Scholar). Suppression of apoptosis may be partially explained by the ability of Bag3 to protect Bcl2 family members against proteasomal degradation (7.Boiani M. Daniel C. Liu X. Hogarty M.D. Marnett L.J. The stress protein BAG3 stabilizes Mcl-1 protein and promotes survival of cancer cells and resistance to antagonist ABT-737.J. Biol. Chem. 2013; 288: 6980-6990Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). In normal cells, Bag3 is constitutively expressed in only a few cell types, including cardiomyocytes (8.Ulbricht A. Eppler F.J. Tapia V.E. van der Ven P.F. Hampe N. Hersch N. Vakeel P. Stadel D. Haas A. Saftig P. Behrends C. Furst D.O. Volkmer R. Hoffmann B. Kolanus W. Hohfeld J. Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy.Curr. Biol. 2013; 23: 430-435Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar). Bag3 is overexpressed in leukemia and several solid tumors where it has been reported to sustain cell survival, induce resistance to therapy, and promote metastasis. The pleiotropic functions of Bag3 may reflect its ability to assemble which in pathways A. V. V. M. a protein that regulates major cell PubMed Scopus Google Scholar). 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Kaya A.M. Wolfrum U. Hartl F.U. Behl C. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3.EMBO J. 2009; 28: 889-901Crossref PubMed Scopus (409) Google Scholar). the of to the role of Bag3 in the induction of senescence with adriamycin Bag3 expression a that Bag3 expression 1 adriamycin as by Bag3 also by In adriamycin-treated cells, Bag3 to the and The level of Bag3 in study the role of Bag3 in Bag3 in control and MCF7 cells a Bag3 the as by analysis The of MCF7 cells that after treatment with adriamycin decreased in Bag3 cells of the cell cycle also observed in Bag3 cells, with control cells with as in the We that Bag3 may a role in apoptosis resistance in senescent cells. 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Bag3 promotes resistance to apoptosis Bcl-2 family members in cell 2012; Google colon cancer (5.Jacobs A.T. Marnett L.J. HSF1-mediated BAG3 expression attenuates apoptosis in 4-hydroxynonenal-treated colon cancer cells via stabilization of anti-apoptotic Bcl-2 proteins.J. Biol. Chem. 2009; 284: 9176-9183Abstract Full Text Full Text PDF PubMed Scopus (132) Google and cell A. V. T. D. Behl C. of genes by in 2013; Google Scholar). We that Bag3 may promote apoptosis resistance in We also the role of Bag3 in when expression of autophagy and after Bag3 demonstrate that Bag3 the senescent phenotype to apoptosis that Bag3 contributes to apoptosis resistance in several that senescent cells to including of and other cellular major protein in senescence-associated apoptosis 2009; PubMed Scopus Google Scholar, G. Bcl-2 a of senescence in J. 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A. senescence: an role PubMed Scopus Google and in senescent cells in which ERK1/2 to promote degradation of proteins cell cycle X. V. F. O. V. S. S. F. A.M. G. suppressor of the pathway by protein 2013; PubMed Scopus Google Scholar). of signaling pathway has also been associated with p53 induced senescence The between senescence and is in by the PubMed Scopus Google Scholar). We observed an increase in adriamycin treatment ERK1/2 and pathways in senescent MCF7 only ERK1/2 in Bag3 and MVP cells that with has been associated with Bag3 and ERK1/2 binds to that may serve as signaling ERK1/2 or in the of to the P. Y. Y. Y. N. Y. X. J. Li Y. W. M. X. X. MVP interacts with and of the Cell Biol. PubMed Scopus Google Scholar). Bag3 has to the interaction of ERK1/2 with 1 in and in its in apoptosis its role is cell A. M. A. A. M. F. V. M. C. A. V. BAG3 of 2012; PubMed Scopus Google Scholar). that MVP and Bag3 promote resistance to apoptosis in senescent cells by or activation of ERK1/2 is a potent survival which in the of cellular cells apoptosis. that silencing in senescent MCF7 cells in apoptosis. functions the cell to regulate diverse including survival, proliferation, and cell In to promote survival, it to the We propose a model in which Bag3 binds to MVP and facilitates MVP accumulation in the nucleus, which sustains ERK1/2 activation. model is in than cell expression of Bag3 and MVP in breast cancer cell including and and Bag3 and MVP expressed and the cell cycle induced after adriamycin treatment in cell lines. a p53 cell the senescence adriamycin treatment as reported M. A. Y. K. A phenotype tumor cells that arrest after to Google Scholar). A recent study on p53 in response to chemotherapy that tumors to arrest to cell death, p53 tumors a senescent demonstrated that the senescent tumors with p53 to chemotherapy than tumors with p53 (4.Jackson J.G. Pant V. Li Q. Chang L.L. Quintas-Cardama A. Garza D. Tavana O. Yang P. Manshouri T. Li Y. El-Naggar A.K. Lozano G. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer.Cancer Cell. 2012; 21: 793-806Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar). A observed in breast to a P. M. A. M. A. J. Y. M. A. The of and breast to a 2007; PubMed Scopus Google Scholar). the response senescence to apoptosis in p53 breast cancer tumors may prove to be therapeutically beneficial. We the of cell in senescent cells after silencing of Bag3 and We observed a increase in apoptosis that Bag3 and MVP the senescent phenotype to apoptosis in p53 cells. We also observed a increase in apoptosis in the and cells after silencing Bag3 or MVP and adriamycin cells a model of breast which to therapy and a than other breast cancer F.J. to breast cancer.Cancer 2013; PubMed Scopus Google Scholar). Bag3 and MVP may contribute to apoptosis resistance and cell survival in and may serve as therapeutic In to Bag3 and MVP regulate ERK1/2 in cell the level of after silencing in cells Bag3 and in cell MVP in MCF7 cells that Bag3 and MVP regulate ERK1/2 prosurvival demonstrated that Bag3 and MVP up-regulated and during We that silencing MVP and Bag3 shifts the cellular response to apoptosis after a of in senescent MCF7 and cells and apoptosis in and breast cancer cell lines. This study Bag3-MVP as an important complex that regulate the ERK1/2 prosurvival signaling that the Bag3-MVP may be a in breast cancer. We the with