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Analysis of the MDM2 antagonist nutlin-3 in human prostate cancer cells

Lookup NU author(s): Dr Ian Logan, Hesta McNeill, Susan Cook, Dr Xiaohong Lu, Professor John Lunec, Professor Craig Robson

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Abstract

BACKGROUND: Small molecule MDM2 antagonists including nutlin-3 have been shown to be effective against a range of cancer cell types and nutlin-3 can inhibit growth of LNCaP xenografts. We compared the efficacy of nutlin-3 in three prostate cancer cell types and provide an insight into the mechanism of nutlin-3. METHODS: Nutlin-3 efficacy was measured using proliferation assays, cell cycle analysis, apoptosis assays, quantitative RT-PCR, and immunoblotting. Chromatin immunoprecipitation (ChIP) assays were also performed. RESULTS: Nutlin-3 can specifically inhibit proliferation of LNCaP cells through cell cycle arrest and apoptosis. This coincides with increased levels of the p53-responsive transcripts p21, PUMA, gadd45, and Mdm2 and recruitment of p53 to chromatin. Nutlin-3 also reduces androgen receptor levels, resulting in altered receptor recruitment to chromatin. CONCLUSION: Our study demonstrates that small molecule MDM2 antagonists might be useful in the treatment of human prostate cancers that retain functional p53 and androgen receptor signaling. © 2007 Wiley-Liss, Inc.


Publication metadata

Author(s): Logan, I., McNeill, H., Cook, S., Lu, X., Lunec, J., Robson, C.N.

Publication type: Article

Publication status: Published

Journal: Prostate

Year: 2007

Volume: 67

Issue: 8

Pages: 900-906

Print publication date: 01/06/2007

ISSN (print): 0270-4137

ISSN (electronic): 1097-0045

URL: http://dx.doi.org/10.1002/pros.20568

DOI: 10.1002/pros.20568

PubMed id: 17440969


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