BAG3-mediated Mcl-1 stabilization contributes to drug resistance via interaction with USP9X in ovarian cancer.
Paclitaxel in combination with carboplatin improves survival among patients with susceptible ovarian cancers, but no strategy has been established against resistant ovarian cancers. BAG3 (Bcl-2-associated athanogene 3) is one of six BAG family proteins, which are involved in such cellular processes as proliferation, migration and apoptosis. In addition, expression of BAG3 with Mcl-1, a Bcl-2 family protein, reportedly associates with resistance to chemotherapy. Our aim in this study was to evaluate the functional role of BAG3 and Mcl-1 in ovarian cancer chemoresistance and explore possible new targets for treatment. We found that combined expression of BAG3 and Mcl-1 was significantly associated with a poor prognosis in ovarian cancer patients. In vitro, BAG3 knockdown in ES2 clear ovarian cancer cells significantly increased the efficacy of paclitaxel in combination with the Mcl-1 antagonist MIM1, with or without the Bcl-2 family antagonist ABT737. Moreover, BAG3 was found to positively regulate Mcl-1 levels by binding to and inhibiting USP9X. Our data show that BAG3 and Mcl-1 are key mediators of resistance to chemotherapy in ovarian cancer. In BAG3 knockdown ES2 clear ovarian cancer cells, combination with ABT737 and MIM1 enhanced the efficacy of paclitaxel. These results suggest that inhibiting BAG3 in addition to anti-apoptotic Bcl-2 family proteins may be a useful therapeutic strategy for the treatment of chemoresistant ovarian cancers.
Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.
Shutaro
S
Habata
Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.
Masahiro
M
Iwasaki
Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.
Asuka
A
Sugio
Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.
Miwa
M
Suzuki
Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.
Masato
M
Tamate
Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.
Seiro
S
Satohisa
Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.
Ryoichi
R
Tanaka
Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.
Tsuyoshi
T
Saito
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis* / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C506234:USP9X protein, human; D043222:Ubiquitin Thiolesterase; D017239:Paclitaxel