Abstract
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.
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Acknowledgements
This work was supported by the Ligue Nationale contre le Cancer (Comité du Rhône), the INCa (Institut National du Cancer) and the Cancéropôle Lyon-Auvergne-Rhône-Alpes (CLARA). F Toscano is a doctoral fellow from the Ligue Nationale contre le Cancer. N Lalaoui is supported by a doctoral joint fellowship from the INSERM and the Conseil Régional de Bourgogne. O Micheau is supported by research grants from the INCa (PL 098), ANR (Agence Nationale de la Recherche, ANR-06-JCJC-0103) and the European Community (ApopTrain Marie Curie RTN). We acknowledge the CeCIL (Centre Commun d'Imagerie Laënnec) for providing part of the technical devices (flow cytometer) used in this work.
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Toscano, F., Fajoui, Z., Gay, F. et al. p53-Mediated upregulation of DcR1 impairs oxaliplatin/TRAIL-induced synergistic anti-tumour potential in colon cancer cells. Oncogene 27, 4161–4171 (2008). https://doi.org/10.1038/onc.2008.52
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DOI: https://doi.org/10.1038/onc.2008.52
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