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J Agric Food Chem. 2016 Mar 2;64(8):1702-11. doi: 10.1021/acs.jafc.5b05668. Epub 2016 Feb 22.

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

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College of Life Science and Technology, Jinan University , Guangzhou, Guangdong 510632, People's Republic of China.
First Affiliated Hospital of Kunming Medical University , Kunming, Yunnan 650032, People's Republic of China.


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.


ROS; calcium release; gypenoside L; unfolded protein response; vacuolation death

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