title: Gypenoside L inhibits autophagic flux and induces cell death in human esophageal cancer cells through endoplasm reticulum stress-mediated Ca2+ release.
abstract: Esophageal cancer is one of the leading cause of cancer mortality in the world. Due to the increased drug and radiation tolerance, it is urgent to develop novel anticancer agent that triggers nonapoptotic cell death to compensate for apoptosis resistance. In this study, we show that treatment with gypenoside L (Gyp-L), a saponin isolated from Gynostemma pentaphyllum, induced nonapoptotic, lysosome-associated cell death in human esophageal cancer cells. Gyp-L-induced cell death was associated with lysosomal swelling and autophagic flux inhibition. Mechanistic investigations revealed that through increasing the levels of intracellular reactive oxygen species (ROS), Gyp-L triggered protein ubiquitination and endoplasm reticulum (ER) stress response, leading to Ca2+ release from ER inositol trisphosphate receptor (IP3R)-operated stores and finally cell death. Interestingly, there existed a reciprocal positive-regulatory loop between Ca2+ release and ER stress in response to Gyp-L. In addition, protein synthesis was critical for Gyp-L-mediated ER stress and cell death. Taken together, this work suggested a novel therapeutic option by Gyp-L through the induction of an unconventional ROS-ER-Ca2+-mediated cell death in human esophageal cancer.
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Chenghui
authors.initials: C
authors.lastname: Liao
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.|College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zheng
authors.affiliation: The First Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Life Sciences, Shenzhen University, Shenzhen, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Qiangrong
authors.initials: Q
authors.lastname: Kang
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Long
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jin
authors.affiliation: The First Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Xuli
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Haiqiang
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Lizhong
authors.initials: L
authors.lastname: Liu
authors.affiliation: The First Affiliated Hospital of School of Medicine, Shenzhen University, Shenzhen, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xiao
authors.affiliation: College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, School of Medicine, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Shenzhen University, Shenzhen, China.
authors.forename: Zhendan
authors.initials: Z
authors.lastname: He
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D029774:Gynostemma; D006801:Humans; D010936:Plant Extracts / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D010936:Plant Extracts; D017382:Reactive Oxygen Species; C474918:gypenoside; D002118:Calcium
keywords: Ca2+ release; ROS; autophagic flux inhibition; unfolded protein response; vacuolation