title: SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells.
abstract: SNX-2112 is an Hsp90 inhibitor which is currently undergoing multiple phase 1 clinical trials; however, its mechanism of action needs to be further elaborated. Here we investigated the effects of SNX-2112 in A-375 cells. SNX-2112 induced the degradation of multiple Hsp90 client proteins, activated both the mitochondrial-mediated and death receptor-mediated apoptotic pathways, downregulated Bcl-2 and Bcl-xL, upregulated Bid, cleaved caspase-9, caspase-7, caspase-3 and PARP, and activated caspase-8. The general caspase inhibitor, z-VAD-fmk, did not completely abolish SNX-2112-induced cell death. SNX-2112 induced autophagy in a time- and dose-dependent manner via Akt/mTOR/p70S6K inhibition. SNX-2112 induces significant apoptosis and autophagy in human melanoma A-375 cells, and may be an effective targeted therapy agent.
authors.affiliation: Guangzhoujinan Biomedicine Research and Development Center, Jinan University, Guangzhou, China.
authors.forename: Kai-Sheng
authors.initials: KS
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Jin-Huan
authors.initials: JH
authors.lastname: Qi
authors.forename: Qiu-Yun
authors.initials: QY
authors.lastname: Liu
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.forename: Guo-Wen
authors.initials: GW
authors.lastname: Xing
authors.forename: Shao-Xiang
authors.initials: SX
authors.lastname: Wang
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008855:Microscopy, Electron, Scanning
chemical_list: D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; C534922:SNX 2112