Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Cancer Lett. 2018 Jan 1;412:46-58. doi: 10.1016/j.canlet.2017.10.006. Epub 2017 Oct 13.
Colon cancer is one of the leading causes of cancer-related deaths. A natural sesquiterpene lactone, costunolide (CTD), showed inhibition of cancer development. However, the underlying mechanisms are not known. Here, we have examined the therapeutic activity and novel mechanisms of the anti-cancer activities of CTD in colon cancer cells. Using SPR analysis and enzyme activity assay on recombinant TrxR1 protein, our results show that CTD directly binds and inhibits the activity of TrxR1, which caused enhanced generation of ROS and led to ROS-dependent endoplasmic reticulum stress and cell apoptosis in colon cancer cells. Overexpression of TrxR1 in HCT116 cells reversed CTD-induced cell apoptosis and ROS increase. CTD treatment of mice implanted with colon cancer cells showed tumor growth inhibition and reduced TrxR1 activity and ROS level. In addition, it was observed that TrxR1 was significantly up-regulated in existing colon cancer gene database and clinically obtained colon cancer tissues. Our studies have uncovered the mechanism underlying the biological activity of CTD in colon cancer and suggest that targeting TrxR1 may prove to be beneficial as a treatment option.
结肠癌是癌症相关死亡的主要原因之一。一种天然的倍半萜内酯，木香烯内酯（CTD），显示出抑制癌症发展的作用。然而，其潜在的机制尚不清楚。在这里，我们研究了 CTD 在结肠癌细胞中的治疗活性和抗癌作用的新机制。使用 SPR 分析和重组 TrxR1 蛋白的酶活性测定，我们的结果表明 CTD 直接结合并抑制 TrxR1 的活性，导致 ROS 的产生增加，并导致 ROS 依赖性内质网应激和细胞凋亡。在 HCT116 细胞中转染 TrxR1 可逆转 CTD 诱导的细胞凋亡和 ROS 增加。CTD 处理植入结肠癌细胞的小鼠显示肿瘤生长抑制和 TrxR1 活性和 ROS 水平降低。此外，在现有的结肠癌基因数据库和临床获得的结肠癌组织中观察到 TrxR1 明显上调。我们的研究揭示了 CTD 在结肠癌中的生物学活性的机制，并表明靶向 TrxR1 可能是一种有益的治疗选择。
