CPX Targeting DJ-1 Triggers ROS-induced Cell Death and Protective Autophagy in Colorectal Cancer
CPX Targeting DJ-1 Triggers ROS-induced Cell Death and Protective Autophagy in Colorectal Cancer
复制标题
CPX 靶向 DJ-1 触发结直肠癌中 ROS 诱导的细胞死亡和保护性自噬
DOI：
10.7150/thno.34663
复制
发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Lei, Yunlong
中科院分区：
文献类型：
--
作者：
Zhou, Jing;Zhang, Lu;Lei, Yunlong
理论基础：结直肠癌(CRC)是全世界最常见的癌症之一。环吡酮胺(CPX)最近被认为是一种很有前途的抗癌候选药物，然而，新的活性和详细的作用机制仍未被发现。方法：体外和体内检测CPX对结直肠癌细胞的杀伤作用。检测对照组和CPX处理组的整体基因表达谱、ROS水平、线粒体功能、自噬、细胞凋亡等。结果：体外和体内实验均发现CPX通过抑制细胞增殖和诱导细胞凋亡来抑制结直肠癌的生长。CPX的抗癌作用涉及下调DJ-1的表达，过表达DJ-1可逆转CPX对大肠癌细胞的细胞毒作用。DJ-1的缺失导致线粒体功能障碍和ROS堆积，从而导致结直肠癌生长抑制。细胞保护性自噬同时被激发，从药物或基因上阻断自噬可以进一步增强CPX的抗癌效果。结论：DJ-1丢失诱导的ROS积聚在CPX介导的结直肠癌抑制中起着关键作用，为进一步了解通过调节代偿性保护性自噬治疗结直肠癌提供了进一步的认识。
Rationale: Colorectal cancer (CRC) is one of the most common cancers worldwide. Ciclopirox olamine (CPX) has recently been identified to be a promising anticancer candidate; however, novel activities and detailed mechanisms remain to be uncovered. Methods: The cytotoxic potential of CPX towards CRC cells was examined in vitro and in vivo. The global gene expression pattern, ROS levels, mitochondrial function, autophagy, apoptosis, etc. were determined between control and CPX-treated CRC cells. Results: We found that CPX inhibited CRC growth by inhibiting proliferation and inducing apoptosis both in vitro and in vivo. The anti-cancer effects of CPX involved the downregulation of DJ-1, and overexpression of DJ-1 could reverse the cytotoxic effect of CPX on CRC cells. The loss of DJ-1 resulted in mitochondrial dysfunction and ROS accumulation, thus leading to CRC growth inhibition. The cytoprotective autophagy was provoked simultaneously, and blocking autophagy pharmacologically or genetically could further enhance the anti-cancer efficacy of CPX. Conclusion: Our study demonstrates that DJ-1 loss-induced ROS accumulation plays a pivotal role in CPX-mediated CRC inhibition, providing a further understanding for CRC treatment via modulating compensatory protective autophagy.