title: The Hsp90 inhibitor SNX-2112 induces apoptosis of human hepatocellular carcinoma cells: the role of ER stress.
abstract: Heat shock protein 90 (Hsp90) has been predicted to be involved in hepatocellular carcinoma (HCC) therapy; however, the mechanisms of action remain elusive. SNX-2112 is an Hsp90 inhibitor showing broad antitumor activity. Here we aim to determine the role of the endoplasmic reticulum (ER) stress in SNX-2112-induced apoptosis in HCC cells. In general, three HCC cells (i.e., HepG2, Huh7, and SK-Hep1) were used in our experiments. The cell viability was determined by the CCK-8 assay. The apoptosis was analyzed using flow cytometry, laser scanning confocal microscopy (LSM) and Western blotting. The efficacy and mechanisms of action of SNX-2112 were also evaluated in a mouse xenograft model. We found that SNX-2112 showed stronger inhibition on cell growth than 17-AAG, a classical Hsp90 inhibitor. SNX-2112 treatment led to the caspase-dependent apoptosis. Interestingly, SNX-2112 decreased the expression levels of the ER chaperone proteins calnexin and immunoglobulin binding protein (BiP). It also inhibited all three ER stress sensors, namely, inositol-requiring gene 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF-6) in vitro and/or in vivo. However, the ER stress inducer tunicamycin strongly enhanced SNX-2112-induced apoptosis, whereas the IRE1 knockdown did not. Taken together, we for the first time indicated the possible apoptotic pathways of SNX-2112 in HCC cells, raising the possibility that the induction of ER stress might be favorable for SNX-2112-induced apoptosis.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Shaoxiang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Weichao
authors.initials: W
authors.lastname: Ding
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Yangfei
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Kaisheng
authors.initials: K
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Yaoying
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Guangzhou Tongde Pharmaceutical Co., Ltd, Guangzhou, Guangdong, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: lssydp@mail.sysu.edu.cn.
authors.forename: Depo
authors.initials: D
authors.lastname: Yang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, Guangdong, China. Electronic address: twang-yf@163.com.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D056945:Hep G2 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; C534922:SNX 2112; D014415:Tunicamycin; D020169:Caspases
keywords: Apoptosis; ER stress; HCC; Hsp90; SNX-2112