Hassan Mohamed, Feyen Oliver, Grinstein Edgar
Laboratory for Experimental Molecular Tumour Therapy, Department of Dermatology, University Hospital of Duesseldorf, Duesseldorf, Germany.
Cell Oncol. 2009;31(6):437-56. doi: 10.3233/CLO-2009-0488.
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 (DeltaPsim), 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.
肾细胞癌（RCC）是化疗难治性肿瘤的典型代表。它仍然是常见泌尿系统癌症中致死率最高的，并且对传统治疗具有高度抗性。在此，我们证实了抗Fas单克隆抗体（CH11）作为治疗RCC的替代治疗方法的有效性，并研究了CH11诱导RCC细胞凋亡的分子机制。本研究表明凋亡信号调节激酶1（ASK1）以及c-jun氨基末端激酶（JNK）和p38途径以及半胱天冬酶-8在此过程中起着至关重要的作用。此外，发现CH11依赖性诱导ASK1-JNK/p38途径可激活转录因子AP-1和ATF-2以及FADD-半胱天冬酶-8-Bid信号传导，导致Bax和Bak蛋白的易位，随后线粒体失调，其特征是线粒体膜电位（ΔΨm）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的裂解。因此，所描述的CH11诱导凋亡的分子机制表明Fas激活作为治疗晚期肾细胞癌患者的替代治疗方法的可靠性。
