The Hsp90 inhibitor SNX-2112 induces apoptosis of human hepatocellular carcinoma cells: the role of ER stress

Xiao Wang, Shaoxiang Wang, Yuting Liu, Weichao Ding, Kai Zheng, Yangfei Xiang, Kaisheng Liu, Dongmei Wang, Yaoying Zeng, Min Xia, Depo Yang, Yifei Wang
Biochemical and Biophysical Research Communications 2014 March 28, 446 (1): 160-6
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.

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