Fas-induced apoptosis of renal cell carcinoma is mediated by apoptosis signal-regulating kinase 1 via mitochondrial damage-dependent caspase-8 activation.
Fas-induced apoptosis of renal cell carcinoma is mediated by apoptosis signal-regulating kinase 1 via mitochondrial damage-dependent caspase-8 activation.
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DOI：
10.3233/clo-2009-0488
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Grinstein E
中科院分区：
文献类型：
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作者：
Hassan M;Feyen O;Grinstein E
肾细胞癌（RCC）是化疗难治性肿瘤的原型。它仍然是最致命的常见泌尿系统癌症，对常规治疗具有高度抗性。在这里，我们证实了抗Fas单克隆抗体（CH 11）作为治疗RCC的替代治疗方法的有效性，并研究了CH 11诱导RCC细胞凋亡的分子机制。目前的研究表明，凋亡信号调节激酶1（ASK 1），连同c-jun-N-末端激酶（JNK）和p38通路，以及caspase-8在这个过程中的重要作用。此外，发现CH 11依赖性诱导的ASK 1-JNK/p38通路激活转录因子AP-1和ATF-2以及FADD-半胱天冬酶-8-Bid信号传导，导致Bax和巴克蛋白易位，随后线粒体失调，其特征在于线粒体膜电位（Δ m）丧失、细胞色素c释放以及半胱天冬酶-9、半胱天冬酶-3和PARP裂解。因此，所描述的CH 11诱导细胞凋亡的分子机制表明Fas活化作为治疗晚期肾细胞癌患者的替代治疗方法的可靠性。
Renal cell carcinoma (RCC) is a prototype of a chemo refractory tumour. It remains the most lethal of the common urologic cancers and is highly resistant to conventional therapy. Here, we confirmed the efficiency of anti-Fas monoclonal antibody (CH11) as alternative therapeutic approach for the treatment of RCC and investigated the molecular mechanism(s), whereby CH11 induces apoptosis of RCC cells. The present study shows an essential role for apoptosis signal-regulating kinase 1 (ASK1), together with both c-jun-N-terminal kinase (JNK) and p38 pathways, and caspase-8 in this process. Furthermore, CH11-dependent induction of the ASK1–JNK/p38 pathways was found to activate the transcription factors AP-1 and ATF-2, and FADD-caspase-8-Bid signalling, resulting in the translocation of both Bax and Bak proteins, and subsequently mitochondrial dysregulation that is characterized by the loss of mitochondrial membrane potential (ΔΨm), cytochrome c release and cleavage of caspase-9, caspase-3 and PARP. Thus, the described molecular mechanisms of CH11-induced apoptosis suggest the reliability of Fas activation as an alternative therapeutic approach for the treatment of patients with advanced renal cell carcinoma.