SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells

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• 作者：Kai-Sheng Liu^a ; ^b ; ^c ; ^d ; ¹ ; Hui Liu^a ; ^b ; ^c ; ¹ ; Jin-Huan Qi^e ; Qiu-Yun Liu^e ; Zhong Liu^a ; ^b ; ^c ; Min Xia^a ; ^b ; ^c ; Guo-Wen Xing^f ; Shao-Xiang Wang^a ; ^b ; ^c ; ^{hackerwsx@163.com} ; Yi-Fei Wang^a ; ^b ; ^c ; ^{twang-yf@163.com}
• 关键词：SNX-2112 ; Hsp90 inhibitor ; Hsp90 client proteins ; Apoptosis ; Autophagy ; A-375
• 刊名：Cancer Letters
• 出版年：2012
• 期刊代码：44_03043835
• 类别：med
• 出版时间：28 May, 2012
• 卷：318
• 期：2
• 页码：180-188
• 文件大小：1335 K

摘要

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.