title: Gypenoside L, Isolated from Gynostemma pentaphyllum, Induces Cytoplasmic Vacuolation Death in Hepatocellular Carcinoma Cells through Reactive-Oxygen-Species-Mediated Unfolded Protein Response.
abstract: 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 Ca(2+) release from endoplasm reticulum (ER) inositol trisphosphate receptor (IP3R)-operated stores and finally cytoplasmic vacuolation and cell death. Interruption of the ROS-ER-Ca(2+) 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-Ca(2+)-mediated cytoplasmic vacuolation death in human HCC.
authors: College of Life Science and Technology, Jinan University , Guangzhou, Guangdong 510632, People's Republic of China.
authors: Kai
authors: K
authors: Zheng
authors: Chenghui
authors: C
authors: Liao
authors: First Affiliated Hospital of Kunming Medical University , Kunming, Yunnan 650032, People's Republic of China.
authors: Yan
authors: Y
authors: Li
authors: Xinmin
authors: X
authors: Fan
authors: Long
authors: L
authors: Fan
authors: Hong
authors: H
authors: Xu
authors: Qiangrong
authors: Q
authors: Kang
authors: First Affiliated Hospital of Kunming Medical University , Kunming, Yunnan 650032, People's Republic of China.
authors: Yong
authors: Y
authors: Zeng
authors: Xuli
authors: X
authors: Wu
authors: Haiqiang
authors: H
authors: Wu
authors: Lizhong
authors: L
authors: Liu
authors: Xiaohua
authors: X
authors: Xiao
authors: Jian
authors: J
authors: Zhang
authors: College of Life Science and Technology, Jinan University , Guangzhou, Guangdong 510632, People's Republic of China.
authors: Yifei
authors: Y
authors: Wang
authors: Zhendan
authors: Z
authors: He
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D029774:Gynostemma / Q000737:chemistry*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects*; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: D010936:Plant Extracts; D017382:Reactive Oxygen Species; C474918:gypenoside
keywords: ROS; calcium release; gypenoside L; unfolded protein response; vacuolation death