Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP
Autor: | Kirsty McLaughlin, Daniel B. Longley, Leeona Galligan, Miranda McEwan, Patrick G. Johnston, Timothy R. Wilson |
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Rok vydání: | 2005 |
Předmět: |
Cancer Research
Colorectal cancer Cell CASP8 and FADD-Like Apoptosis Regulating Protein Apoptosis Decoy Receptor 1 Pharmacology Biology Receptors Tumor Necrosis Factor Tumor Cells Cultured medicine Null cell Humans Cytotoxic T cell RNA Small Interfering Receptor DNA Primers Base Sequence Intracellular Signaling Peptides and Proteins Cancer Flow Cytometry medicine.disease medicine.anatomical_structure Oncology Colonic Neoplasms Tumor Suppressor Protein p53 |
Zdroj: | Molecular Cancer Therapeutics. 4:2026-2036 |
ISSN: | 1538-8514 1535-7163 |
DOI: | 10.1158/1535-7163.mct-05-0262 |
Popis: | Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has recently attracted attention as a potential therapeutic agent in the treatment of cancer. We assessed the roles of p53, TRAIL receptors, and cellular Fas-associated death domain–like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) in regulating the cytotoxic effects of recombinant TRAIL (rTRAIL) alone and in combination with chemotherapy [5-fluorouracil (5-FU), oxaliplatin, and irinotecan] in a panel of colon cancer cell lines. Using clonogenic survival and flow cytometric analyses, we showed that chemotherapy sensitized p53 wild-type, mutant, and null cell lines to TRAIL-mediated apoptosis. Although chemotherapy treatment did not modulate mRNA or cell surface expression of the TRAIL receptors death receptor 4, death receptor 5, decoy receptor 1, or decoy receptor 2, it was found to down-regulate expression of the caspase-8 inhibitor, c-FLIP. Stable overexpression of the long c-FLIP splice form but not the short form was found to inhibit chemotherapy/rTRAIL–induced apoptosis. Furthermore, siRNA-mediated down-regulation of c-FLIP, particularly the long form, was found to sensitize colon cancer cells to rTRAIL-induced apoptosis. In addition, treatment of a 5-FU-resistant cell line with 5-FU down-regulated c-FLIP expression and sensitized the chemotherapy-resistant cell line to rTRAIL. We conclude that TRAIL-targeted therapies may be used to enhance conventional chemotherapy regimens in colon cancer regardless of tumor p53 status. Furthermore, inhibition of c-FLIP may be a vital accessory strategy for the optimal use of TRAIL-targeted therapies. [Mol Cancer Ther 2005;4(12):2026–36] |
Databáze: | OpenAIRE |
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