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Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells
- Source :
- Oncogene. 27:76-84
- Publication Year :
- 2007
- Publisher :
- Springer Science and Business Media LLC, 2007.
-
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.
- Subjects :
- Cancer Research
Programmed cell death
CASP8 and FADD-Like Apoptosis Regulating Protein
Down-Regulation
Uterine Cervical Neoplasms
medicine.disease_cause
Genetics
medicine
Humans
RNA, Small Interfering
Protein kinase A
Molecular Biology
Caspase
MAP kinase kinase kinase
biology
Tumor Necrosis Factor-alpha
JNK Mitogen-Activated Protein Kinases
HCT116 Cells
Enzyme Activation
Apoptosis
Tumor progression
Caspases
Cancer research
biology.protein
Female
Tumor necrosis factor alpha
Reactive Oxygen Species
Carcinogenesis
HeLa Cells
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....592f2ce978cb52ffabb728396bc24547