Department of Pathology and Research Institute of Oriental Medicine, Dongeui University College of Oriental Medicine, Busan 614-052, Republic of Korea.
Toxicol Lett. 2012 Aug 3;212(3):252-61. doi: 10.1016/j.toxlet.2012.06.007. Epub 2012 Jun 18.
Selenium in the form of sodium selenite has been reported to exert anti-tumor effects in several cancer cell types by inducing autophagic cell death and apoptosis mediated by reactive oxygen species (ROS). However, the exact molecular pathways underlying these effects have not been fully established. The present study used A549 human lung carcinoma cells for further investigation of the anti-cancer mechanism of sodium selenite. We showed that sodium selenite modulated both the extrinsic and intrinsic apoptotic pathways, which were interconnected by Bid truncation. We used z-VAD-fmk, a pan-caspase inhibitor, to demonstrate that sodium selenite-induced apoptosis was dependent on the activation of caspases. Sodium selenite also increased autophagy, as indicated by an increase in microtubule-associated protein light chain-3 (LC3) puncta, accumulation of LC3II, and elevation of autophagic flux. Pretreatment with bafilomycin A1 enhanced sodium selenite-induced apoptosis, indicating that sodium selenite-induced autophagy functioned as a survival mechanism. Sodium selenite treatment also resulted in generation of ROS, which abrogated mitochondrial membrane potential (MMP) and regulated both apoptosis and autophagy. Phospho-nuclear factor erythroid 2-related factor 2 (p-Nrf2) showed a ROS-dependent translocation to the nucleus, which suggested that Nrf2 might increase cell survival by suppressing ROS accumulation and apoptosis mediated by oxidative stress. Sodium selenite treatment of A549 cells therefore appeared to trigger both apoptosis and cytoprotective autophagy, which were both mediated by ROS. The data suggest that regulation of ROS generation and autophagy can be a potential strategy for treating lung cancer that is resistant to pro-apoptotic therapeutics.
亚硒酸钠以硒酸钠的形式被报道在几种癌细胞类型中通过诱导活性氧（ROS）介导的自噬细胞死亡和细胞凋亡发挥抗肿瘤作用。然而，这些作用的确切分子途径尚未完全建立。本研究使用 A549 人肺癌细胞进一步研究亚硒酸钠的抗癌机制。我们表明，亚硒酸钠调节了外在和内在的凋亡途径，这两种途径通过 Bid 截断相互连接。我们使用 z-VAD-fmk（一种广谱半胱天冬酶抑制剂）证明亚硒酸钠诱导的细胞凋亡依赖于半胱天冬酶的激活。亚硒酸钠还增加了自噬，如微管相关蛋白轻链 3（LC3）点状增加、LC3II 积累和自噬通量升高所表明的那样。用巴弗洛霉素 A1 预处理增强了亚硒酸钠诱导的细胞凋亡，表明亚硒酸钠诱导的自噬作为一种生存机制发挥作用。亚硒酸钠处理还导致 ROS 的产生，这破坏了线粒体膜电位（MMP）并调节凋亡和自噬。磷酸化核因子红细胞 2 相关因子 2（p-Nrf2）显示出 ROS 依赖性核转位，这表明 Nrf2 可能通过抑制 ROS 积累和氧化应激介导的细胞凋亡来增加细胞存活。因此，亚硒酸钠处理 A549 细胞似乎触发了凋亡和细胞保护自噬，这两者均由 ROS 介导。数据表明，调节 ROS 的产生和自噬可能是治疗对促凋亡治疗有抗性的肺癌的一种潜在策略。
