c-FLIP inhibits chemotherapy-induced colorectal cancer cell death
| Autor: | Leeona Galligan, Miranda McEwan, Patrick G. Johnston, Wendy L. Allen, Timothy R. Wilson, Daniel B. Longley, Ultan McDermott |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
Programmed cell death Cell CASP8 and FADD-Like Apoptosis Regulating Protein Down-Regulation Antineoplastic Agents Apoptosis Caspase 8 medicine.disease_cause Receptors Tumor Necrosis Factor TNF-Related Apoptosis-Inducing Ligand Downregulation and upregulation Tumor Cells Cultured Genetics medicine Humans Protein Splicing fas Receptor RNA Small Interfering Molecular Biology Caspase Membrane Glycoproteins Cell Death biology Tumor Necrosis Factor-alpha Intracellular Signaling Peptides and Proteins Caspase Inhibitors Receptors TNF-Related Apoptosis-Inducing Ligand medicine.anatomical_structure Cell culture Caspases Mutation Immunology Cancer research biology.protein Tumor Suppressor Protein p53 Apoptosis Regulatory Proteins Colorectal Neoplasms Carcinogenesis |
| Zdroj: | Oncogene. 25:838-848 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1209122 |
| Popis: | c-FLIP inhibits caspase 8 activation and apoptosis mediated by death receptors such as Fas and DR5. We studied the effect of c-FLIP on the apoptotic response to chemotherapies used in colorectal cancer (CRC) (5-fluorouracil, oxaliplatin and irinotecan). Simultaneous downregulation of both c-FLIP splice forms c-FLIP(L) and c-FLIP(S) with siRNA synergistically enhanced chemotherapy-induced apoptosis in p53 wild-type (HCT116p53(+/+), RKO), null (HCT116p53(-/-)) and mutant (H630) CRC cell lines. Furthermore, overexpression of c-FLIP(L), but not c-FLIP(S), potently inhibited apoptosis induced by chemotherapy in HCT116p53(+/+) cells, suggesting that c-FLIP(L) was the more important splice form in mediating chemoresistance. In support of this, siRNA specifically targeted against c-FLIP(L) synergistically enhanced chemotherapy-induced apoptosis in a manner similar to the siRNA targeted against both splice forms. Inhibition of caspase 8 blocked the enhanced apoptosis induced by c-FLIP-targeted (FT) siRNA and chemotherapy. Furthermore, we found that downregulating cell surface DR5, but not Fas, also inhibited apoptosis induced by FT siRNA and chemotherapy. Interestingly, these effects were not dependent on activation of DR5 by its ligand TRAIL. These results indicate that c-FLIP inhibits TRAIL-independent, DR5- and caspase 8-dependent apoptosis in response to chemotherapy in CRC cells. Moreover, targeting c-FLIP in combination with existing chemotherapies may have therapeutic potential for the treatment of CRC. |
| Databáze: | OpenAIRE |
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