Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells.

Abstract

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.

• Authors: A Nakajima, Y Kojima, M Nakayama, H Yagita, K Okumura, H Nakano
• Journal: Oncogene (Oncogene) Vol. 27 Issue 1 Pg. 76-84 (Jan 03 2008) ISSN: 1476-5594 [Electronic] England
• PMID: 17599041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• RNA, Small Interfering
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• JNK Mitogen-Activated Protein Kinases
• Caspases

Topics

• CASP8 and FADD-Like Apoptosis Regulating Protein (antagonists & inhibitors, deficiency, genetics, physiology)
• Caspases (physiology)
• Down-Regulation (genetics)
• Enzyme Activation (physiology)
• Female
• HCT116 Cells
• HeLa Cells
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• RNA, Small Interfering (genetics)
• Reactive Oxygen Species (metabolism)
• Tumor Necrosis Factor-alpha (physiology)
• Uterine Cervical Neoplasms (enzymology, genetics, metabolism)