Zou Peng, Xia Yiqun, Chen Weiqian, Chen Xi, Ying Shilong, Feng Zhiguo, Chen Tongke, Ye Qingqing, Wang Zhe, Qiu Chenyu, Yang Shulin, Liang Guang
School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Oncotarget. 2016 Apr 5;7(14):18050-64. 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 deï¬ned. 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.
胃癌（GC）是全球癌症死亡的主要原因之一，因此迫切需要找到治疗晚期胃癌的新型药物。二苯基二氟甲酮（EF24）是一种结构与姜黄素相似的分子，通过阻滞细胞周期和诱导凋亡展现出强大的抗肿瘤活性。尽管EF24在多种人类癌细胞中显示出强大的抗癌功效，但其细胞靶点尚未完全明确。我们在此报告，EF24可能与硫氧还蛋白还原酶1（TrxR1）相互作用，TrxR1是一种重要的含硒代半胱氨酸（Sec）的抗氧化酶，可诱导人胃癌细胞中活性氧（ROS）介导的凋亡。通过抑制TrxR1活性并增加细胞内ROS水平，EF24在人胃癌细胞中诱导致命的内质网应激。重要的是，敲低TrxR1可使细胞对EF24治疗敏感。在体内，EF24治疗可显著降低TrxR1活性和肿瘤细胞负荷，并与5-氟尿嘧啶（5-FU）对胃癌细胞显示出协同致死作用。因此，用EF24靶向TrxR1揭示了EF24生物活性背后一种先前未被认识的机制，并表明TrxR1是胃癌治疗的一个良好靶点。
