p53 potentiation of tumor cell susceptibility to CTL involves Fas and mitochondrial pathways
p53 potentiation of tumor cell susceptibility to CTL involves Fas and mitochondrial pathways
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DOI：
10.4049/jimmunol.174.2.871
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发表时间：
2005-01-15
影响因子：
4.4
通讯作者：
Chouaib, S
中科院分区：
文献类型：
--
作者：
Thiery, J;Abouzahr, S;Chouaib, S
在这项研究中，我们研究了野生型p53 （wtp53）增强肿瘤细胞对ctl介导的细胞死亡的易感性的机制。我们报道，在Gustave Roussy研究所(IGR)-Heu的人肺癌细胞系中，显示p53突变，导致Fas/CD95受体表达上调，与肿瘤细胞对自体CTL克隆Heu127的敏感性增加相关。然而，当用Fas cDNA转染IGR-Heu细胞时，没有观察到heu127介导的裂解增强，这表明诱导CD95不足以使靶细胞对CTL杀伤敏感。重要的是，我们的数据表明wtp53对fas介导途径的影响涉及短细胞FLICE抑制蛋白的降解，导致随后的caspase 8激活。此外，我们证明wtp53恢复也导致ctl诱导的Bid易位进入线粒体，随后线粒体膜渗透导致细胞色素c释放。这些结果表明，通过恢复wtp53（凋亡机制调节的关键决定因素），靶向脱颗粒非依赖性机制可以增强自体CTL对肿瘤细胞的杀伤作用。
In this study, we have investigated the mechanisms used by wild-type p53 (wtp53) to potentiate tumor cell susceptibility to CTL-mediated cell death. We report that wtp53 restoration in a human lung carcinoma cell line Institut Gustave Roussy (IGR)-Heu, displaying a mutated p53, resulted in up-regulation of Fas/CD95 receptor expression associated with an increase of tumor cell sensitivity to the autologous CTL clone, Heu127. However, when IGR-Heu cells were transfected with Fas cDNA, no potentiation to Heu127-mediated lysis was observed, indicating that induction of CD95 is not sufficient to sensitize target cells to CTL killing. Importantly, our data indicate that the effect of wtp53 on the Fas-mediated pathway involves a degradation of short cellular FLICE inhibitory protein resulting in subsequent caspase 8 activation. Furthermore, we demonstrate that wtp53 restoration also resulted in CTL-induced Bid translocation into mitochondria and a subsequent mitochondrial membrane permeabilization leading to cytochrome c release. These results indicate that tumor cell killing by autologous CTL can be enhanced by targeting degranulation-independent mechanisms via restoration of wtp53, a key determinant of apoptotic machinery regulation.