Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells
Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells
复制标题
DOI：
10.1038/sj.onc.1210624
复制
发表时间：
2008-01-03
期刊：
影响因子：
8
通讯作者：
Nakano, H.
中科院分区：
文献类型：
--
作者：
Nakajima, A.;Kojima, Y.;Nakano, H.
核因子-kappaB通过抑制caspase级联、c-jun氨基末端激酶(JNK)途径和活性氧(ROS)积累来抑制细胞死亡。抑制核因子-kappaB的这种抗凋亡功能可能是增加肿瘤细胞对应激诱导细胞死亡的易感性的一种有前途的策略。我们最近发现，肿瘤坏死因子(TNF)α可诱导细胞内c-Flip(-/-)小鼠胚胎成纤维细胞(MEF)中caspase依赖和非依赖的JNK激活和ROS积聚。为了将这一观察结果应用于肿瘤治疗，我们通过在各种肿瘤细胞中进行RNA干扰来抑制c-flip。与c-Flip(-/-)MEF的结果一致，我们发现，在各种肿瘤细胞中，肿瘤坏死因子α刺激诱导caspase依赖的JNK激活和ROS积聚延长，继而导致细胞凋亡和坏死。此外，在c-flip基因敲除细胞中，肿瘤坏死因子α和Fas诱导丝裂原激活的蛋白激酶/ERK激酶(MEKK)1的裂解，导致MEKK1结构活性的产生，从而激活JNK。鉴于ROS积聚和坏死性细胞死亡促进炎症反应和肿瘤细胞代偿性增殖，选择性抑制依赖caspase的ROS积聚将是保护细胞免受ROS依赖的DNA损伤和代偿性肿瘤进展的替代策略。
Nuclear factor-kappa B (NF-kappa B) inhibits cell death through suppression of the caspase cascade, the c-Jun N-terminal kinase (JNK) pathway, and reactive oxygen species (ROS) accumulation. To suppress this antiapoptotic function of NF-kappa B might be a promising strategy to increase susceptibility of tumor cells to stress-induced cell death. We have recently shown that tumor necrosis factor (TNF)alpha induces caspase-dependent and -independent JNK activation and ROS accumulation in cellular FLICE-inhibitory protein (c-Flip)(-/-) murine embryonic fibroblasts (MEFs). To apply this observation to tumor therapy, we knocked down c-FLIP by RNA interference in various tumor cells. Consistent with the results using c-Flip(-/-) MEFs, we found that TNF alpha stimulation induced caspase-dependent prolonged JNK activation and ROS accumulation, followed by apoptotic and necrotic cell death in various tumor cells. Furthermore, TNF alpha and Fas induced the cleavage of mitogen-activated protein kinase/ ERK kinase kinase (MEKK)1, resulting in generation of a constitutive active form of MEKK1 leading to JNK activation in c-FLIP knockdown cells. Given that ROS accumulation and necrotic cell death enhance inflammation followed by compensatory proliferation of tumor cells, selective suppression of caspase-dependent ROS accumulation will be an alternative strategy to protect cells from ROS-dependent DNA damage and compensatory tumor progression.