Cisplatin-induced necroptosis in TNFα. dependent and independent pathways
Cisplatin-induced necroptosis in TNFα. dependent and independent pathways
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TNFα 依赖和独立途径中顺铂诱导的坏死性凋亡
DOI：
10.1016/j.cellsig.2017.01.004
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发表时间：
2017-02-01
影响因子：
4.8
通讯作者：
Chen, Rui-qing
中科院分区：
文献类型：
--
作者：
Xu, Yanfang;Ma, Hua-bin;Chen, Rui-qing
顺铂是一种用于治疗多种实体瘤的化疗药物。它已显示在不同类型的癌细胞中诱导凋亡和/或坏死。然而，根本的机制仍然难以捉摸。在这项研究中，我们提供的证据表明，顺铂诱导受体相互作用蛋白3（RIP 3）表达细胞系的坏死性凋亡，而不是在缺乏RIP 3蛋白表达的细胞系。在L929细胞中，坏死性凋亡途径的核心组分、里皮、RIP 3或混合谱系激酶结构域样蛋白（MLKL）的缺乏阻断顺铂诱导的细胞死亡。这种现象依赖于RIP 1/RIP 3/MLKL坏死体形成和易位至线粒体相关膜（MAM），但仅部分通过肿瘤坏死因子α（TNF α）的自分泌产生。此外，我们证明了线粒体通透性转换孔开放（mPTP）开放和活性氧（ROS）的产生是顺铂诱导的坏死性凋亡中坏死体形成的关键下游事件，这是TNF α独立的。亲环素D（CypD）缺乏可部分减少顺铂诱导的细胞死亡，表明CypD介导的mPTP开放在顺铂诱导的坏死性凋亡中起重要作用。CypD和TNFa两者的缺失。完全阻断顺铂诱导的细胞死亡，表明顺铂可通过TNF α依赖和非依赖途径诱导坏死性凋亡。这些发现为顺铂诱导的坏死性凋亡的分子机制提供了新的见解。(C)2017爱思唯尔公司All rights reserved.
Cisplatin is a chemotherapeutic drug for treatment of many solid tumors. It has been shown to induce apoptosis and/or necrosis in different types of cancer cells. However, the underlying mechanisms remain elusive. In this study, we provide evidences that cisplatin induces necroptosis in receptor-interacting protein 3 (RIP3)-expressing cell lines, but not in cell lines lacking RIP3 protein expression. Deficiency of core components of necroptotic pathway, RIPI, RIP3, or mixed lineage kinase domain-like protein (MLKL) blocked cisplatin-induced cell death in L929 cells. This phenomenon is dependent on RIP1/RIP3/MLKL necrosome formation and translocation to mitochondria -associated membrane (MAM), but only partially via autocrine production of tumor necrosis factor a (TNF alpha). Moreover, we demonstrate that the mitochondrial permeability transition pore opening (mPTP) opening and reactive oxygen species (ROS) generation is a critical downstream event of the formation of necrosome in cisplatin-induced necroptosis, which is TNFa independent. Deficiency of cyclophilin-D (CypD) partially reduced cisplatin-induced cell death, indicating CypD mediated-mPTP opening plays an important role during cisplatin-induced necroptosis. Both deletion of CypD and TNFa. completely blocked cisplatin-induced cell death, suggesting that cisplatin could induce necroptosis through TNFa dependent and independent pathway. These findings provide new insight into the molecular mechanisms underlying cisplatin-induced necroptosis. (C) 2017 Elsevier Inc. All rights reserved.