Selective killing of gastric cancer cells by a small molecule via targeting TrxR1 and ROS-mediated ER stress activation
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Weiqian Chen1,2,*, Peng Zou1,3,*, Zhongwei Zhao2, Qiaoyou Weng2, Xi Chen1, Shilong Ying1, Qingqing Ye1, Zhe Wang1, Jiansong Ji2, Guang Liang1
1Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
2Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China
3School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, 210094, China
*These authors have contributed equally to this work
Guang Liang, e-mail: email@example.com
Jiansong Ji, e-mail: firstname.lastname@example.org
Keywords: thioredoxin reductase 1, reactive oxygen species (ROS), gastric cancer, ER stress, mitochondrial dysfunction
Received: October 22, 2015 Accepted: February 05, 2016 Published: February 22, 2016
The thioredoxin reductase (TrxR) 1 is often overexpressed in numerous cancer cells. Targeting TrxR1 leads to a reduction in tumor progression and metastasis, making the enzyme an attractive target for cancer treatment. Our previous research revealed that the curcumin derivative B19 could induce cancer cell apoptosis via activation of endoplasmic reticulum (ER) stress. However, the upstream mechanism and molecular target of B19 is still unclear. In this study, we demonstrate that B19 directly inhibits TrxR1 enzyme activity to elevate oxidative stress and then induce ROS-mediated ER Stress and mitochondrial dysfunction, subsequently resulting in cell cycle arrest and apoptosis in human gastric cancer cells. A computer-assistant docking showed that B19 may bind TrxR1 protein via formation of a covalent bond with the residue Cys-498. Blockage of ROS production totally reversed B19-induced anti-cancer actions. In addition, the results of xenograft experiments in mice were highly consistent with in vitro studies. Taken together, targeting TrxR1 with B19 provides deep insight into the understanding of how B19 exerts its anticancer effects. More importantly, this work indicates that targeting TrxR1 and manipulating ROS levels are effective therapeutic strategy for the treatment of gastric cancer.
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