p53-Mediated upregulation of DcR1 impairs oxaliplatin/TRAIL-induced synergistic anti-tumour potential in colon cancer cells
| Autor: | F Toscano, Z El Fajoui, F Gay, N Lalaoui, B Parmentier, J-A Chayvialle, J-Y Scoazec, O Micheau, J Abello, J-C Saurin |
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| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Programmed cell death Organoplatinum Compounds Colorectal cancer Apoptosis Biology GPI-Linked Proteins medicine.disease_cause TNF-Related Apoptosis-Inducing Ligand Downregulation and upregulation Antineoplastic Combined Chemotherapy Protocols Receptors Tumor Necrosis Factor Member 10c Tumor Cells Cultured Genetics medicine Humans Molecular Biology Cancer Drug Synergism HCT116 Cells medicine.disease digestive system diseases Up-Regulation Oxaliplatin Gene Expression Regulation Neoplastic Tumor Necrosis Factor Decoy Receptors Drug Resistance Neoplasm Colonic Neoplasms Cancer cell Immunology Cancer research Mutant Proteins Tumor Suppressor Protein p53 Carcinogenesis Drug Antagonism HT29 Cells medicine.drug |
| Zdroj: | Oncogene. 27:4161-4171 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2008.52 |
| Popis: | Oxaliplatin has emerged as a major chemotherapeutic drug in the treatment of advanced colorectal cancer, yet like most conventional cancer therapeutics, its efficacy is often compromised due to p53 mutations. Unlike oxaliplatin, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a p53-independent manner, and chemotherapy is known to overcome tumour resistance to TRAIL-induced cell death in most cancer cells. Using a panel of colon cancer cell lines, we assessed the ability of oxaliplatin to sensitize to TRAIL-induced apoptosis. We demonstrate that while both drugs additively or synergistically induced apoptosis in almost all cell lines tested, p53 wild-type colon cancer cells such as HCT116, LS513 or LS174T remained resistant. Impaired TRAIL-induced cell death resulted from a strong p53 dependent, oxaliplatin-mediated, DcR1 receptor expression increase. According to our finding, downregulation of DcR1 using siRNA, in p53 wild-type colon cancer cells, restored oxaliplatin/TRAIL synergistic apoptotic activity. On the contrary, exogenous DcR1 overexpression in SW480, a p53-mutated cell line, abolished the synergy between the two drugs. Altogether we demonstrate for the first time that p53 negatively regulates oxaliplatin-mediated TRAIL-induced apoptotic activity through DcR1 upregulation. Our findings could have important implications for future therapeutic strategies, and suggest that the association oxaliplatin/TRAIL should be restricted to patients harbouring a non-functional p53 protein. |
| Databáze: | OpenAIRE |
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