title: Hsp90 inhibitor 17-AAG sensitizes Bcl-2 inhibitor (-)-gossypol by suppressing ERK-mediated protective autophagy and Mcl-1 accumulation in hepatocellular carcinoma cells.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, 30 Gaotanyan, Shapingba, Chongqing 400038, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Blood Transfusion, PLA General Hospital, Beijing 100853, China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, 30 Gaotanyan, Shapingba, Chongqing 400038, China.
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Ni
authors.affiliation: Department of Educational Science College, Chongqing Normal University, Chongqing 400047, China.
authors.forename: Xufang
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, 30 Gaotanyan, Shapingba, Chongqing 400038, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, 30 Gaotanyan, Shapingba, Chongqing 400038, China.
authors.forename: Yaran
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, 30 Gaotanyan, Shapingba, Chongqing 400038, China.
authors.forename: Xinzhe
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments of Molecular Biosciences and Radiation Oncology, University of Kansas Cancer Center, University of Kansas, Lawrence, 66045-7534, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Jiqin
authors.initials: J
authors.lastname: Lian
authors.affiliation: 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.
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D016227:Benzoquinones / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006072:Gossypol / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C477012:MAP1LC3A protein, human; C579095:MCL1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C112765:tanespimycin; D048049:Extracellular Signal-Regulated MAP Kinases; D006072:Gossypol
keywords: (-)-Gossypol; Autophagy; Bcl-2; ERK; Hsp90