Gypenoside L, Isolated from Gynostemma pentaphyllum, Induces Cytoplasmic Vacuolation Death in Hepatocellular Carcinoma Cells through Reactive-Oxygen-Species-Mediated Unfolded Protein Response

详细信息    查看全文

• 作者：Kai Zheng ; Chenghui Liao ; Yan Li ; Xinmin Fan ; Long Fan ; Hong Xu ; Qiangrong Kang ; Yong Zeng ; Xuli Wu ; Haiqiang Wu ; Lizhong Liu ; Xiaohua Xiao ; Jian Zhang ; Yifei Wang ; Zhendan He
• 刊名：Journal of Agricultural and Food Chemistry
• 出版年：2016
• 出版时间：March 2, 2016
• 年：2016
• 卷：64
• 期：8
• 页码：1702-1711
• 全文大小：742K
• ISSN：1520-5118

文摘

Exploring novel anticancer agents that can trigger non-apoptotic or non-autophagic cell death is urgent for cancer treatment. In this study, we screened and identified an unexplored anticancer activity of gypenoside L (Gyp-L) isolated from Gynostemma pentaphyllum. We showed that treatment with Gyp-L induces non-apoptotic and non-autophagic cytoplasmic vacuolation death in human hepatocellular carcinoma (HCC) cells. Mechanically, Gyp-L initially increased the intracellular reactive oxygen species (ROS) levels, which, in turn, triggered protein ubiquitination and unfolded protein response (UPR), resulting in Ca²⁺ release from endoplasm reticulum (ER) inositol trisphosphate receptor (IP₃R)-operated stores and finally cytoplasmic vacuolation and cell death. Interruption of the ROS–ER–Ca²⁺ signaling pathway by chemical inhibitors significantly prevented Gyp-L-induced vacuole formation and cell death. In addition, Gyp-L-induced ER stress and vacuolation death required new protein synthesis. Overall, our works provide strong evidence for the anti-HCC activity of Gyp-L and suggest a novel therapeutic option by Gyp-L through the induction of a unconventional ROS–ER–Ca²⁺-mediated cytoplasmic vacuolation death in human HCC.