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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.
MedLine Citation:
PMID:  23187459     Owner:  NLM     Status:  Publisher    
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.
Eun Jung Park; Kyeong Sook Choi; Young Hyun Yoo; Taeg Kyu Kwon
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-25
Journal Detail:
Title:  Anti-cancer drugs     Volume:  -     ISSN:  1473-5741     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
aDepartment of Immunology, School of Medicine, Keimyung University, Daegu bDepartment of Molecular Science and Technology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon cDepartment of Anatomy and Cell Biology, Mitochondrial Hub Regulation Center, College of Medicine, Dong-A University, Busan, South Korea.
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