Nakajima A, Kojima Y, Nakayama M, Yagita H, Okumura K, Nakano H
Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Oncogene. 2008 Jan 3;27(1):76-84. doi: 10.1038/sj.onc.1210624. Epub 2007 Jun 25.
Nuclear factor-kappa B (NF-kappaB) 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-kappaB 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 TNFalpha stimulation induced caspase-dependent prolonged JNK activation and ROS accumulation, followed by apoptotic and necrotic cell death in various tumor cells. Furthermore, TNFalpha 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.
核因子-κB（NF-κB）通过抑制半胱天冬酶级联反应、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NF-κB的这种抗凋亡功能可能是一种增加肿瘤细胞对应激诱导的细胞死亡敏感性的有前景的策略。我们最近发现肿瘤坏死因子（TNF）α在细胞型FLICE抑制蛋白（c-Flip）基因敲除（-/-）的小鼠胚胎成纤维细胞（MEF）中诱导半胱天冬酶依赖性和非依赖性的JNK激活以及ROS积累。为了将这一观察结果应用于肿瘤治疗，我们通过RNA干扰在各种肿瘤细胞中敲低c-FLIP。与使用c-Flip（-/-）MEF的结果一致，我们发现TNFα刺激在各种肿瘤细胞中诱导半胱天冬酶依赖性的JNK延长激活和ROS积累，随后是凋亡性和坏死性细胞死亡。此外，TNFα和Fas诱导丝裂原活化蛋白激酶/细胞外信号调节激酶激酶激酶（MEKK）1的裂解，导致在c-FLIP敲低细胞中产生持续活化形式的MEKK1从而导致JNK激活。鉴于ROS积累和坏死性细胞死亡会增强炎症反应，随后导致肿瘤细胞的代偿性增殖，选择性抑制半胱天冬酶依赖性的ROS积累将是一种保护细胞免受ROS依赖性DNA损伤和代偿性肿瘤进展的替代策略。
