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

• Published in: Oncotarget Vol. 7; no. 14; pp. 18050 - 18064
• Main Authors: Zou, Peng, Xia, Yiqun, Chen, Weiqian, Chen, Xi, Ying, Shilong, Feng, Zhiguo, Chen, Tongke, Ye, Qingqing, Wang, Zhe, Qiu, Chenyu, Yang, Shulin, Liang, Guang
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 05.04.2016
• Subjects: Animals; Apoptosis - drug effects; Benzylidene Compounds - pharmacology; Cell Line, Tumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Piperidones - pharmacology; Reactive Oxygen Species - metabolism; Research Paper; Stomach Neoplasms - drug therapy; Stomach Neoplasms - enzymology; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Thioredoxin Reductase 1 - antagonists & inhibitors; Thioredoxin Reductase 1 - metabolism; Xenograft Model Antitumor Assays; ER stress; thioredoxin reductase 1; EF24; gastric cancer; reactive oxygen species
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.7633

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 effïcacy 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.