The stress protein BAG3 stabilizes Mcl-1 protein and promotes survival of cancer cells and resistance to antagonist ABT-737.

Boiani M, Daniel C, Liu X, Hogarty MD, Marnett LJ
J Biol Chem. 2013 288 (10): 6980-90

PMID: 23341456 · PMCID: PMC3591608 · DOI:10.1074/jbc.M112.414177

Members of the Bcl-2 family of proteins are important inhibitors of apoptosis in human cancer and are targets for novel anticancer agents such as the Bcl-2 antagonists, ABT-263 (Navitoclax), and its analog ABT-737. Unlike Bcl-2, Mcl-1 is not antagonized by ABT-263 or ABT-737 and is considered to be a major factor in resistance. Also, Mcl-1 exhibits differential regulation when compared with other Bcl-2 family members and is a target for anticancer drug discovery. Here, we demonstrate that BAG3, an Hsp70 co-chaperone, protects Mcl-1 from proteasomal degradation, thereby promoting its antiapoptotic activity. Using neuroblastoma cell lines, with a defined Bcl-2 family dependence, we found that BAG3 expression correlated with Mcl-1 dependence and ABT-737 resistance. RNA silencing of BAG3 led to a marked reduction in Mcl-1 protein levels and overcame ABT-737 resistance in Mcl-1-dependent cells. In ABT-737-resistant cells, Mcl-1 co-immunoprecipitated with BAG3, and loss of Mcl-1 after BAG3 silencing was prevented by proteasome inhibition. BAG3 and Mcl-1 were co-expressed in a panel of diverse cancer cell lines resistant to ABT-737. Silencing BAG3 reduced Mcl-1 protein levels and overcame ABT-737 resistance in several of the cell lines, including triple-negative breast cancer (MDA-MB231) and androgen receptor-negative prostate cancer (PC3) cells. These studies identify BAG3-mediated Mcl-1 stabilization as a potential target for cancer drug discovery.

MeSH Terms (25)

Adaptor Proteins, Signal Transducing Antineoplastic Agents Apoptosis Apoptosis Regulatory Proteins Biphenyl Compounds Cell Line, Tumor Cell Survival Drug Resistance, Neoplasm Gene Expression Regulation, Neoplastic HEK293 Cells Humans Immunoblotting Myeloid Cell Leukemia Sequence 1 Protein Neoplasms Nitrophenols Piperazines Proteasome Endopeptidase Complex Protein Binding Protein Stability Proteolysis Proto-Oncogene Proteins c-bcl-2 Reverse Transcriptase Polymerase Chain Reaction RNA Interference Sulfonamides Ubiquitination

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