Induction of apoptosis and autophagy by sodium selenite in A549 human lung carcinoma cells through generation of reactive oxygen species
Induction of apoptosis and autophagy by sodium selenite in A549 human lung carcinoma cells through generation of reactive oxygen species
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DOI：
10.1016/j.toxlet.2012.06.007
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发表时间：
2012-08-03
影响因子：
3.5
通讯作者：
Choi, Yung Hyun
中科院分区：
文献类型：
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作者：
Park, Shin-Hyung;Kim, Jeong-Hwan;Choi, Yung Hyun
据报道，亚硒酸钠形式的硒通过诱导自噬性细胞死亡和活性氧（ROS）介导的凋亡在几种癌细胞类型中发挥抗肿瘤作用。然而，这些效应背后的确切分子途径尚未完全建立。本研究以A549人肺癌细胞为研究对象，进一步探讨亚硒酸钠的抗癌机制。我们发现，亚硒酸钠调制的外在和内在的凋亡途径，这是相互联系的投标截断。我们使用z-VAD-favorite，一种泛半胱天冬酶抑制剂，证明亚硒酸钠诱导的细胞凋亡依赖于半胱天冬酶的激活。亚硒酸钠也增加了自噬，如微管相关蛋白轻链-3（LC 3）斑点的增加，LC 3 II的积累和自噬通量的升高所示。巴弗洛霉素A1预处理增强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。亚硒酸钠处理还导致ROS的产生，其废除线粒体膜电位（MMP）并调节细胞凋亡和自噬。磷酸化核因子红细胞2相关因子2（p-Nrf 2）显示ROS依赖性的核转位，这表明Nrf 2可能通过抑制ROS积累和氧化应激介导的凋亡来增加细胞存活。因此，亚硒酸钠处理的A549细胞似乎触发细胞凋亡和细胞保护性自噬，这两者都是由ROS介导的。这些数据表明，ROS生成和自噬的调节可以是治疗对促凋亡疗法有抗性的肺癌的潜在策略。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
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. (C) 2012 Elsevier Ireland Ltd. All rights reserved.