Oncotarget

Research Papers:

EF24 induces ROS-mediated apoptosis via targeting thioredoxin reductase 1 in gastric cancer cells

Peng Zou, Yiqun Xia, Weiqian Chen, Xi Chen, Shilong Ying, Zhiguo Feng, Tongke Chen, Qingqing Ye, Zhe Wang, Chenyu Qiu, Shulin Yang and Guang Liang _

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Oncotarget. 2016; 7:18050-18064. https://doi.org/10.18632/oncotarget.7633

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Abstract

Peng Zou1,2,*, Yiqun Xia3,*, Weiqian Chen2, Xi Chen2, Shilong Ying2, Zhiguo Feng2, Tongke Chen2, Qingqing Ye2, Zhe Wang2, Chenyu Qiu2, Shulin Yang1 and Guang Liang2

1 School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, China

2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China

3 Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

* These authors have contributed equally to this work

Correspondence to:

Guang Liang, email:

Shulin Yang, email:

Keywords: thioredoxin reductase 1, reactive oxygen species, EF24, ER stress, gastric cancer

Received: December 03, 2015 Accepted: February 14, 2016 Published: February 23, 2016

Abstract

Gastric cancer (GC) is one of the leading causes of cancer mortality in the world, and finding novel agents for the treatment of advanced gastric cancer is of urgent need. Diphenyl difluoroketone (EF24), a molecule having structural similarity to curcumin, exhibits potent anti-tumor activities by arresting cell cycle and inducing apoptosis. Although EF24 demonstrates potent anticancer efficacy in numerous types of human cancer cells, the cellular targets of EF24 have not been fully defined. We report here that EF24 may interact with the thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, to induce reactive oxygen species (ROS)-mediated apoptosis in human gastric cancer cells. By inhibiting TrxR1 activity and increasing intracellular ROS levels, EF24 induces a lethal endoplasmic reticulum stress in human gastric cancer cells. Importantly, knockdown of TrxR1 sensitizes cells to EF24 treatment. In vivo, EF24 treatment markedly reduces the TrxR1 activity and tumor cell burden, and displays synergistic lethality with 5-FU against gastric cancer cells. Targeting TrxR1 with EF24 thus discloses a previously unrecognized mechanism underlying the biological activity of EF24, and reveals that TrxR1 is a good target for gastric cancer therapy.


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