Endoplasmic reticulum stress triggers delanzomib-induced apoptosis in HCC cells through the PERK/eIF2α/ATF4/CHOP pathway.
Jun Li, Jianyong Zhuo, Wei Zhou, Jiawei Hong, Ronggao Chen, Haiyang Xie, Lin Zhou, Shusen Zheng, Donghai Jiang
Abstract
For limited clinical benefits and acquired resistance by sorafenib, new therapeutic strategies and molecular targets for the treatment of advanced hepatocellular carcinoma (HCC) are urgently needed. This study aimed to evaluate the potential antitumor effects of the second-generation proteasome inhibitor delanzomib on HCC. The results demonstrated that delanzomib displayed excellent antitumor activity on HCC cells with sensitivity or resistance to sorafenib in a time- and dose-response manner, by inducing G2/M cell cycle arrest and apoptosis in vitro. Cell cycle arrest was associated with the activation of p21/Cdc2/cyclin B1 pathway, and cell apoptosis was confirmed by PARP and caspase-3 cleavage. In addition, delanzomib induced endoplasmic reticulum stress (ERS) in HCC cells by activating the PERK and ERS-associated proteins including p-eIF2α, ATF4 and CHOP. Selective inhibition of eIF2α dephosphorylation by salubrinal could significantly reduce delanzomib-induced apoptosis in HCC cells. In vivo, delanzomib could also exhibit effective antitumor properties on patient-derived xenograft mouse model of HCC with relative low drug-associated cytotoxicity. Compared to control group, 3 and 10 mg/kg of delanzomib significantly reduced the tumor volume by 33.1% and 87.2% respectively after 3 weeks treatment, with no significant change on the body weight and the level of serum biochemical indexes including ALT, AST and BUN. In conclusion, delanzomib could exhibit good pre-clinical antitumor effects against HCC cells by inducing ERS and activating the PERK/eIF2α/ATF4/CHOP pathway, as potential drug candidate on treatment of advanced HCC patients.