Alkannin induces cytotoxic autophagy and apoptosis by promoting ROS-mediated mitochondrial dysfunction and activation of JNK pathway
Alkannin induces cytotoxic autophagy and apoptosis by promoting ROS-mediated mitochondrial dysfunction and activation of JNK pathway
复制标题
Alkannin 通过促进 ROS 介导的线粒体功能障碍和 JNK 通路激活来诱导细胞毒性自噬和细胞凋亡
DOI：
10.1016/j.bcp.2020.114167
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发表时间：
2020
影响因子：
5.8
通讯作者：
Lin Ping
中科院分区：
文献类型：
--
作者：
Zheng Qianwen;Li Qin;Zhao Gang;Zhang Jie;Yuan Hang;Gong Di;Guo Yafei;Liu Xinhua;Li Kai;Lin Ping
萘醌衍生物及其代谢产物是自然界中广泛分布的分子。紫草素是一种天然的萘醌化合物，在癌细胞中诱导优异的细胞毒性。然而，紫草素抑制癌细胞存活的详细机制仍不清楚。在本研究中，我们从紫草中分离出紫草素，发现紫草素以剂量依赖的方式诱导多种类型的癌细胞的细胞毒性自噬和凋亡。紫草素处理导致细胞内活性氧（ROS）的积累增加，导致线粒体膜电位损失，氧化损伤和JNK和p38 MAPK通路激活。值得注意的是，我们发现p38 MAPK和JNK信号在紫草素介导的细胞凋亡和自噬的调节中具有拮抗作用。抗氧化剂NAC有效地减弱紫草素诱导的细胞毒性和下游信号通路的激活。此外，紫草素增强了癌细胞对化疗药物的敏感性。总之，我们的研究突出了紫草素的显著广谱抗肿瘤作用，并揭示了紫草素通过促进ROS介导的线粒体功能障碍和JNK通路激活诱导细胞毒性自噬和凋亡的重要机制。
Naphthoquinone derivatives and metabolites are widely dispersed molecules in nature. Alkannin, a natural naphthoquinone compound, induces excellent cytotoxicity in cancer cells. However, the detailed mechanism by which alkannin inhibits cancer cell survival remains unclear. In the present study, we isolated alkannin fromArnebia euchromaand found that alkannin induced cytotoxic autophagy and apoptosis in many types of cancer cells in a dose-dependent manner. Alkannin treatment resulted in elevated accumulation of intracellular reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, oxidative damage and JNK and p38 MAPK pathway activation. Notably, we found an antagonistic pattern of p38 MAPK and JNK signaling in the regulation of alkannin-mediated apoptosis and autophagy. Antioxidant NAC effectively attenuated alkannin-induced cytotoxicity and activation of downstream signaling pathways. Moreover, alkannin enhanced the sensitivity of cancer cells to chemotherapeutic agents. In summary, our study highlights the significant broad-spectrum antitumor effects of alkannin and reveals an important mechanism by which alkannin induces cytotoxic autophagy and apoptosis by promoting ROS-mediated mitochondrial dysfunction and activation of the JNK pathway.