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Nutlin-3, a small-molecule MDM2 inhibitor, sensitizes Caki cells to TRAIL-induced apoptosis through p53-mediated PUMA upregulation and ROS-mediated DR5 upregulation.

Park, EJ; Choi, KS; Yoo, YH; Kwon, TK
Anti-cancer drugs, 24(3):260-269, 2013
Journal Title
Anti-cancer drugs
Nutlin-3 is a novel small-molecule antagonist of the human homolog of mouse double minute (MDM2) that binds MDM2 in the p53-binding pocket and activates the p53 signaling pathway. In this study, we show that nutlin-3 sensitizes Caki human renal cancer cells, but not normal human skin fibroblast (HSF) cells or human mesangial cells, to TRAIL-mediated apoptosis. Combined treatment with nutlin-3 and TRAIL markedly induces apoptosis in HCT116 cells (p53 wild type), but not in HCT116 p53-/- cells, suggesting that p53 is critical for the sensitizing effect of nutlin-3 on TRAIL-induced apoptosis. Pretreatment with N-acetylcysteine (NAC) significantly inhibited nutlin-3-induced DR5 upregulation and cell death induced by the combined treatment with nutlin-3 and TRAIL, suggesting that reactive oxygen species (ROS) mediate nutlin-3-induced DR5 upregulation, which contributes toward TRAIL-mediated apoptosis. However, the upregulation of the p53-mediated protein p53 upregulated modulator of apoptosis (PUMA) by nutlin-3 is likely to be ROS independent because antioxidants failed to block PUMA upregulation. Interestingly, a combined treatment with NAC and PUMA small interfering RNAs significantly blocks nutlin-3-induced and TRAIL-induced apoptosis. Therefore, the present study shows that nutlin-3 enhances TRAIL-induced apoptosis in human renal cancer cells by ROS-mediated or p53-mediated DR5 upregulation and p53-induced PUMA upregulation. These results may offer a novel therapeutic approach to TRAIL-based cancer therapy.
MeSH terms
Acetylcysteine/pharmacologyApoptosis/*drug effects/physiologyApoptosis Regulatory Proteins/*metabolismCell Line, TumorFibroblasts/drug effects/metabolismGenes, p53HCT116 Cells/drug effectsHumansImidazoles/*pharmacologyKidney Neoplasms/drug therapy/metabolism/pathologyPiperazines/*pharmacologyProto-Oncogene Proteins/*metabolismProto-Oncogene Proteins c-mdm2/*antagonists & inhibitorsReactive Oxygen Species/metabolismReceptors, TNF-Related Apoptosis-Inducing Ligand/*metabolismTNF-Related Apoptosis-Inducing Ligand/metabolism/pharmacologyUp-Regulation/drug effects
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Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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