Hsp70-Bag3 Interactions Regulate Cancer-related Signaling Networks

Overview

Journal Cancer Res

Specialty Oncology

Date 2014 Jul 5

PMID 24994713

Citations 100

Authors

Teresa A Colvin

Vladimir L Gabai

Jianlin Gong

Stuart K Calderwood

Hu Li

Suryaram Gummuluru

Olga N Matchuk

Svetlana G Smirnova

Nina V Orlova

Irina A Zamulaeva

Mikel Garcia-Marcos

Xiaokai Li

Z T Young

Jennifer N Rauch

Jason E Gestwicki

Shinichi Takayama

Michael Y Sherman

Affiliations

Soon will be listed here.

Abstract

Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anticancer target.

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References

Massey A, Williamson D, Browne H, Murray J, Dokurno P, Shaw T . A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol. 2009; 66(3):535-45. DOI: 10.1007/s00280-009-1194-3. View

Kim Y, Koo K, Sung J, Yun U, Kim H . Anoikis resistance: an essential prerequisite for tumor metastasis. Int J Cell Biol. 2012; 2012:306879. PMC: 3296207. DOI: 10.1155/2012/306879. View

Ammirante M, Rosati A, Arra C, Basile A, Falco A, Festa M . IKK{gamma} protein is a target of BAG3 regulatory activity in human tumor growth. Proc Natl Acad Sci U S A. 2010; 107(16):7497-502. PMC: 2867736. DOI: 10.1073/pnas.0907696107. View

Beere H, Wolf B, Cain K, Mosser D, Mahboubi A, Kuwana T . Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol. 2000; 2(8):469-75. DOI: 10.1038/35019501. View

Rousaki A, Miyata Y, Jinwal U, Dickey C, Gestwicki J, Zuiderweg E . Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones. J Mol Biol. 2011; 411(3):614-32. PMC: 3146629. DOI: 10.1016/j.jmb.2011.06.003. View

Ciocca D, Calderwood S . Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones. 2005; 10(2):86-103. PMC: 1176476. DOI: 10.1379/csc-99r.1. View

Chen X, Shen B, Xia L, Khaletzkiy A, Chu D, Wong J . Activation of nuclear factor kappaB in radioresistance of TP53-inactive human keratinocytes. Cancer Res. 2002; 62(4):1213-21. View

Itahana K, Campisi J, Dimri G . Mechanisms of cellular senescence in human and mouse cells. Biogerontology. 2004; 5(1):1-10. DOI: 10.1023/b:bgen.0000017682.96395.10. View

Hunt C, Dix D, Sharma G, Pandita R, Gupta A, Funk M . Genomic instability and enhanced radiosensitivity in Hsp70.1- and Hsp70.3-deficient mice. Mol Cell Biol. 2004; 24(2):899-911. PMC: 343815. DOI: 10.1128/MCB.24.2.899-911.2004. View

10.

Wang A, Miyata Y, Klinedinst S, Peng H, Chua J, Komiyama T . Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat Chem Biol. 2012; 9(2):112-8. PMC: 3552084. DOI: 10.1038/nchembio.1140. View

11.

Calderwood S, Khaleque M, Sawyer D, Ciocca D . Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci. 2006; 31(3):164-72. DOI: 10.1016/j.tibs.2006.01.006. View

12.

Chen Y, Yang L, Cheng L, Tu S, Guo S, Le H . Bcl2-associated athanogene 3 interactome analysis reveals a new role in modulating proteasome activity. Mol Cell Proteomics. 2013; 12(10):2804-19. PMC: 3790292. DOI: 10.1074/mcp.M112.025882. View

13.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

14.

Ulbricht A, Eppler F, Tapia V, van der Ven P, Hampe N, Hersch N . Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy. Curr Biol. 2013; 23(5):430-5. DOI: 10.1016/j.cub.2013.01.064. View

15.

Wang Z, Gall J, Bonegio R, Havasi A, Hunt C, Sherman M . Induction of heat shock protein 70 inhibits ischemic renal injury. Kidney Int. 2011; 79(8):861-70. PMC: 8006160. DOI: 10.1038/ki.2010.527. View

16.

Michels A, Kanon B, Konings A, Ohtsuka K, Bensaude O, Kampinga H . Hsp70 and Hsp40 chaperone activities in the cytoplasm and the nucleus of mammalian cells. J Biol Chem. 1998; 272(52):33283-9. DOI: 10.1074/jbc.272.52.33283. View

17.

Li S . Specificity and versatility of SH3 and other proline-recognition domains: structural basis and implications for cellular signal transduction. Biochem J. 2005; 390(Pt 3):641-53. PMC: 1199657. DOI: 10.1042/BJ20050411. View

18.

Gentilella A, Khalili K . BAG3 expression in glioblastoma cells promotes accumulation of ubiquitinated clients in an Hsp70-dependent manner. J Biol Chem. 2011; 286(11):9205-15. PMC: 3059025. DOI: 10.1074/jbc.M110.175836. View

19.

Rerole A, Gobbo J, de Thonel A, Schmitt E, Pais de Barros J, Hammann A . Peptides and aptamers targeting HSP70: a novel approach for anticancer chemotherapy. Cancer Res. 2011; 71(2):484-95. DOI: 10.1158/0008-5472.CAN-10-1443. View

20.

Yaglom J, Gabai V, Sherman M . High levels of heat shock protein Hsp72 in cancer cells suppress default senescence pathways. Cancer Res. 2007; 67(5):2373-81. DOI: 10.1158/0008-5472.CAN-06-3796. View