Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells.
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.
Nakajima
A
A
Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Kojima
Y
Y
Nakayama
M
M
Yagita
H
H
Okumura
K
K
Nakano
H
H
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020169:Caspases / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases