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Exp Cell Res. 2014 Nov 1;328(2):379-87. doi: 10.1016/j.yexcr.2014.08.039. Epub 2014 Sep 6.

Hsp90 inhibitor 17-AAG sensitizes Bcl-2 inhibitor (-)-gossypol by suppressing ERK-mediated protective autophagy and Mcl-1 accumulation in hepatocellular carcinoma cells.

Author information

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.
5
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, 30 Gaotanyan, Shapingba, Chongqing 400038, China. Electronic address: lianjiqin@sina.com.
6
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, 30 Gaotanyan, Shapingba, Chongqing 400038, China. Electronic address: hefengtian06@aliyun.com.

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-1(Thr163) 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.

KEYWORDS:

(-)-Gossypol; Autophagy; Bcl-2; ERK; Hsp90

PMID:
25196280
DOI:
10.1016/j.yexcr.2014.08.039
[Indexed for MEDLINE]

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