Hsp90 inhibitor 17-AAG sensitizes Bcl-2 inhibitor (-)-gossypol by suppressing ERK-mediated protective autophagy and Mcl-1 accumulation in hepatocellular carcinoma cells |
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Authors: | Bin Wang Linfeng Chen Zhenhong Ni Xufang Dai Liyan Qin Yaran Wu Xinzhe Li Liang Xu Jiqin Lian Fengtian He |
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Institution: | 1. Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, 30 Gaotanyan, Shapingba, Chongqing 400038, China;2. Department of Blood Transfusion, PLA General Hospital, Beijing 100853, China;3. Department of Educational Science College, Chongqing Normal University, Chongqing 400047, China;4. Departments of Molecular Biosciences and Radiation Oncology, University of Kansas Cancer Center, University of Kansas, Lawrence, 66045-7534, USA |
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Abstract: | Natural BH3-memitic (-)-gossypol shows promising antitumor efficacy in several kinds of cancer. However, our previous studies have demonstrated that protective autophagy decreases the drug sensitivities of Bcl-2 inhibitors in hepatocellular carcinoma (HCC) cells. In the present study, we are the first to report that Hsp90 inhibitor 17-AAG enhanced (-)-gossypol-induced apoptosis via suppressing (-)-gossypol-triggered protective autophagy and Mcl-1 accumulation. The suppression effect of 17-AAG on autophagy was mediated by inhibiting ERK-mediated Bcl-2 phosphorylation while was not related to Beclin1 or LC3 protein instability. Meanwhile, 17-AAG downregulated (-)-gossypol-triggered Mcl-1 accumulation by suppressing Mcl-1Thr163 phosphorylation and promoting protein degradation. Collectively, our study indicates that Hsp90 plays an important role in tumor maintenance and inhibition of Hsp90 may become a new strategy for sensitizing Bcl-2-targeted chemotherapies in HCC cells. |
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Keywords: | HCC hepatocellular carcinoma Hsp90 heat shock protein 90 Bcl-2 B-cell lymphoma-2 LC3 microtubule-associated protein 1 light chain 3 CQ chloroquine ERK extracellular regulated kinase |
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