Autocrine TNFα signaling renders human cancer cells susceptible to smac-mimetic-induced apoptosis
Autocrine TNFα signaling renders human cancer cells susceptible to smac-mimetic-induced apoptosis
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DOI：
10.1016/j.ccr.2007.08.029
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发表时间：
2007-11-01
期刊：
影响因子：
50.3
通讯作者：
Wang, Xiaodong
中科院分区：
文献类型：
--
作者：
Petersen, Sean L.;Wang, Lai;Wang, Xiaodong
Smac/Diablo的小分子模拟物特异性对抗IAP蛋白的细胞凋亡抑制活性，已显示可增强细胞表面死亡受体以及化疗药物诱导的细胞凋亡。令人惊讶的是，对一组50个人非小细胞肺癌细胞系的调查显示，大约四分之一的这些细胞系对单独的Smac模拟物的治疗敏感，这表明在这些细胞中已经打开了凋亡信号，并被IAP蛋白控制。这种信号现在被鉴定为自分泌的细胞因子肿瘤坏死因子α（TNF α）。响应于自分泌TNF α信号传导，Smac模拟物促进RIPK 1依赖性胱天蛋白酶-8激活复合物的形成，导致细胞凋亡。
A small-molecule mimetic of Smac/Diablo that specifically counters the apoptosis-inhibiting activity of IAP proteins has been shown to enhance apoptosis induced by cell surface death receptors as well as chemotherapeutic drugs. Survey of a panel of 50 human non-small-cell lung cancer cell lines has revealed, surprisingly, that roughly one-quarter of these lines are sensitive to the treatment of Smac mimetic alone, suggesting that an apoptotic signal has been turned on in these cells and is held in check by IAP proteins. This signal has now been identified as the autocrine-secreted cytokine tumor necrosis factor alpha (TNF alpha). In response to autocrine TNFa signaling, the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis.