6-shogaol induces apoptosis in human hepatocellular carcinoma cells and exhibits anti-tumor activity in vivo through endoplasmic reticulum stress6-shogaol人类肝癌细胞发生凋亡展品通过内质网应激体内抗肿瘤活性.pdfVIP

6-Shogaol Induces Apoptosis in Human Hepatocellular Carcinoma Cells and Exhibits Anti-Tumor Activity In Vivo through Endoplasmic Reticulum Stress 1. 1. 1 1 1 1 1 1 Rong Hu , Ping Zhou , Yong-Bo Peng , Xiaojun Xu , Jiang Ma , Qun Liu , Lei Zhang , Xiao-Dong Wen , 1 2 1 Lian-Wen Qi , Ning Gao *, Ping Li * 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China, 2 Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China Abstract 6-Shogaol is an active compound isolated from Ginger (Zingiber officinale Rosc). In this work, we demonstrated that 6- shogaol induces apoptosis in human hepatocellular carcinoma cells in relation to caspase activation and endoplasmic reticulum (ER) stress signaling. Proteomic analysis revealed that ER stress was accompanied by 6-shogaol-induced apoptosis in hepatocellular carcinoma cells. 6-shogaol affected the ER stress signaling by regulating unfolded protein response (UPR) sensor PERK and its downstream target eIF2a. However, the effect on the other two UPR sensors IRE1 and ATF6 was not obvious. In prolonged ER stress, 6-shogaol inhibited the phosphorylation of eIF2a and triggered apoptosis in SMMC-7721 cells. Salubrinal, an activator of the PERK/eIF2a pathway, strikingly enhanced the phosphorylation of eIF2a in SMMC-7721 cells with no toxicity. However, combined treatment with 6-shogaol and salubrinal resulted in significantly increase of apoptosis and dephosphorylation of eIF2a. Overexpression of eIF2a prevented 6-shogaol-mediated apoptosis in SMMC- 7721 cells, whereas inhibition of eIF2a by small in