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- Title
Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells.
- Authors
Nakajima, A.; Kojima, Y.; Nakayama, M.; Yagita, H.; Okumura, K.; Nakano, H.
- Abstract
Nuclear factor-kappa B (NF-κB) 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-κB 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)α 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 TNFα stimulation induced caspase-dependent prolonged JNK activation and ROS accumulation, followed by apoptotic and necrotic cell death in various tumor cells. Furthermore, TNFα 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.Oncogene (2008) 27, 76–84; doi:10.1038/sj.onc.1210624; published online 25 June 2007
- Subjects
NF-kappa B; TUMORS; CELLS; PROTEIN kinases; NECROSIS
- Publication
Oncogene, 2008, Vol 27, Issue 1, p76
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1210624