Mitochondrial inhibitor sensitizes non-small-cell lung carcinoma cells to TRAIL-induced apoptosis by reactive oxygen species and Bcl-X(L)/p53-mediated amplification mechanisms.
Mitochondrial inhibitor sensitizes non-small-cell lung carcinoma cells to TRAIL-induced apoptosis by reactive oxygen species and Bcl-X(L)/p53-mediated amplification mechanisms.
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线粒体抑制剂通过活性氧和 Bcl-X(L)/p53 介导的放大机制使非小细胞肺癌细胞对 TRAIL 诱导的细胞凋亡敏感。
DOI：
10.1038/cddis.2014.547
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发表时间：
2014-12-18
影响因子：
9
通讯作者：
Yin W
中科院分区：
文献类型：
--
作者：
Shi YL;Feng S;Chen W;Hua ZC;Bian JJ;Yin W
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）是一种很有前途的抗肿瘤药物，但非小细胞肺癌（non-small-cell lung carcinoma，NSCLC）细胞对TRAIL的耐药率较高。鉴定可以恢复NSCLC对TRAIL诱导的细胞凋亡的易感性的小分子是有意义的。我们发现鱼藤酮作为线粒体呼吸抑制剂，在亚毒性浓度下优先增加NSCLC细胞对TRAIL介导的凋亡的敏感性，其机制是通过上调死亡受体和下调c-FLIP（细胞FLICE样抑制蛋白）来解释的。进一步的分析显示，鱼藤酮引起的死亡受体表达受p53的调节，而c-FLIP的下调则被Bcl-XL的过表达所阻断。鱼藤酮触发了源自于拟南芥的活性氧（ROS）的产生，随后导致Bcl-XL下调和Bcl-A上调。由于p53调控p53的表达，鱼藤酮处理的细胞中的p53、Bcl-XL和p53形成正反馈放大环，从而增加凋亡敏感性。然而，线粒体衍生的ROS促进这种放大环的形成。总的来说，我们的结论是，ROS的产生，Bcl-XL和p53介导的扩增机制有一个重要的作用，在敏感的NSCLC细胞的TRAIL介导的细胞凋亡鱼藤酮。联合TRAIL和鱼藤酮治疗可能被认为是治疗NSCLC的有用方法，值得进一步研究。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for anticancer therapy; however, non-small-cell lung carcinoma (NSCLC) cells are relatively TRAIL resistant. Identification of small molecules that can restore NSCLC susceptibility to TRAIL-induced apoptosis is meaningful. We found here that rotenone, as a mitochondrial respiration inhibitor, preferentially increased NSCLC cells sensitivity to TRAIL-mediated apoptosis at subtoxic concentrations, the mechanisms by which were accounted by the upregulation of death receptors and the downregulation of c-FLIP (cellular FLICE-like inhibitory protein). Further analysis revealed that death receptors expression by rotenone was regulated by p53, whereas c-FLIP downregulation was blocked by Bcl-XL overexpression. Rotenone triggered the mitochondria-derived reactive oxygen species (ROS) generation, which subsequently led to Bcl-XL downregulation and PUMA upregulation. As PUMA expression was regulated by p53, the PUMA, Bcl-XL and p53 in rotenone-treated cells form a positive feedback amplification loop to increase the apoptosis sensitivity. Mitochondria-derived ROS, however, promote the formation of this amplification loop. Collectively, we concluded that ROS generation, Bcl-XL and p53-mediated amplification mechanisms had an important role in the sensitization of NSCLC cells to TRAIL-mediated apoptosis by rotenone. The combined TRAIL and rotenone treatment may be appreciated as a useful approach for the therapy of NSCLC that warrants further investigation.