P53-mediated upregulation of DcR1 impairs oxaliplatin/TRAIL-induced synergistic anti-tumour potential in colon cancer cells.
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.
Toscano
F
F
INSERM, U865, Institut Fédératif de Recherche Lyon Est, Lyon, F-69372, France; Univ. Lyon 1, Faculté Laënnec, Lyon, F-69008, France.
Fajoui
Z El
ZE
Gay
F
F
Lalaoui
N
N
Parmentier
B
B
Chayvialle
J-A
JA
Scoazec
J-Y
JY
Micheau
O
O
Abello
J
J
Saurin
J-C
JC
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004336:Drug Antagonism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D058851:GPI-Linked Proteins; D050505:Mutant Proteins; D009944:Organoplatinum Compounds; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C108661:TNFRSF10C protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin