1. ¹INSERM, U865, Institut Fédératif de Recherche Lyon Est, Lyon, F-69372, France; Univ. Lyon 1, Faculté Laënnec, Lyon, F-69008, France
2. ²INSERM, U866, Dijon, F21079, France; Univ. Bourgogne, Dijon, F-21079, France

Correspondence: Dr J Abello, INSERM Unité 865, Faculté de Médecine Laënnec, 7 rue G. Paradin, F-69372 Lyon Cedex 08, France. E-mail: abello@lyon.inserm.fr

³These authors contributed equally to this work.

Received 16 July 2007; Revised 20 December 2007; Accepted 28 January 2008; Published online 17 March 2008.

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.