Resistance to the cytotoxic effects of tumor necrosis factor α can be overcome by inhibition of a FADD/caspase-dependent signaling pathway
Resistance to the cytotoxic effects of tumor necrosis factor α can be overcome by inhibition of a FADD/caspase-dependent signaling pathway
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DOI：
10.1074/jbc.274.51.36817
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发表时间：
1999-12-17
影响因子：
4.8
通讯作者：
Tatton, L
中科院分区：
文献类型：
--
作者：
Khwaja, A;Tatton, L
肿瘤坏死因子(TNF) α启动促凋亡途径的激活，涉及含有死亡结构域蛋白FADD的募集和随后特定蛋白酶（半胱天冬酶）的激活。然而，由于涉及转录因子NP κ B和TRAF2的促生存途径的同时激活，许多细胞对TNF α的细胞毒性作用具有抗性。本研究表明，TNF α激活的FADD/caspase通路也能发挥意想不到的促生存作用。在NIH3T3成纤维细胞或U937白血病细胞中，通过肽半胱天冬酶抑制剂或显性阴性FADD表达抑制该途径可导致TNF α治疗后快速死亡，而对照细胞则具有TNF α抗性。FADD/caspase抑制细胞死亡的非凋亡机制是由于活性氧的产生增加，导致线粒体膜电位丧失。细胞毒性可通过包括还原型谷胱甘肽在内的抗氧化剂预孵育或通过表达显性阴性Rac gtp结合蛋白来预防。这些结果表明，caspase在响应TNF α时的激活具有抗坏死和促凋亡的作用，并扩展了我们对这些蛋白酶的生物学作用的理解。
Tumor necrosis factor (TNF) alpha initiates the activation of a pro-apoptotic pathway involving the recruitment of the death domain containing protein FADD and the subsequent activation of specific proteases (caspases). Many cells are resistant, however, to the cytotoxic effects of TNF alpha due to the concurrent activation of pro-survival pathways involving the transcription factor NP kappa B and TRAF2. Here we show that the TNF alpha-activated FADD/caspase pathway can also exert an unexpected pro-survival effect. Inhibition of this pathway in NIH3T3 fibroblasts or U937 leukemic cells by peptide caspase inhibitors or expression of dominant-negative FADD leads to rapid death following treatment with TNF alpha, whereas control cells are TNF alpha-resistant. FADD/caspase inhibited cells die by a non-apoptotic mechanism caused by increased production of reactive oxygen species which precedes loss of the mitochondrial membrane potential. Cytotoxicity can be prevented by preincubation with antioxidants including reduced glutathione or by expression of a dominant-negative Rac GTP-binding protein. These results indicate that caspase activation in response to TNF alpha as anti-necrotic as well as pro-apoptotic effects and extend our understanding of the biological role of these proteases.