Oncotarget

Research Papers:

Gypenoside L inhibits autophagic flux and induces cell death in human esophageal cancer cells through endoplasm reticulum stress-mediated Ca2+ release

Chenghui Liao, Kai Zheng, Yan Li, Hong Xu, Qiangrong Kang, Long Fan, Xiaopeng Hu, Zhe Jin, Yong Zeng, Xiaoli Kong, Jian Zhang, Xuli Wu, Haiqiang Wu, Lizhong Liu, Xiaohua Xiao, Yifei Wang and Zhendan He _

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Oncotarget. 2016; 7:47387-47402. https://doi.org/10.18632/oncotarget.10159

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Abstract

Chenghui Liao1,*, Kai Zheng1,2,*, Yan Li3, Hong Xu4, Qiangrong Kang1, Long Fan1, Xiaopeng Hu1, Zhe Jin1, Yong Zeng3, Xiaoli Kong1, Jian Zhang1, Xuli Wu1, Haiqiang Wu1, Lizhong Liu1, Xiaohua Xiao5, Yifei Wang2, Zhendan He1

1Department 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

2College of Life Science and Technology, Jinan University, Guangzhou, China

3The First Affiliated Hospital of Kunming Medical University, Kunming, China

4College of Life Sciences, Shenzhen University, Shenzhen, China

5The First Affiliated Hospital of School of Medicine, Shenzhen University, Shenzhen, China

*These authors contributed equally to this work

Correspondence to:

Zhendan He, email: [email protected]

Yifei Wang, email: [email protected]

Kai Zheng, email: [email protected]

Keywords: ROS, unfolded protein response, autophagic flux inhibition, vacuolation, Ca2+ release

Received: November 08, 2015     Accepted: June 06, 2016     Published: June 18, 2016

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.


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