title: Selective killing of gastric cancer cells by a small molecule via targeting TrxR1 and ROS-mediated ER stress activation.
abstract: 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.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.|Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
authors.forename: Weiqian
authors.initials: W
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.|School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, 210094, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.affiliation: Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
authors.forename: Qiaoyou
authors.initials: Q
authors.lastname: Weng
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Shilong
authors.initials: S
authors.lastname: Ying
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Ji
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D003474:Curcumin
keywords: ER stress; gastric cancer; mitochondrial dysfunction; reactive oxygen species (ROS); thioredoxin reductase 1