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Analysis of the MDM2 antagonist nutlin-3 in human prostate cancer cells
Ian R Logan1, Hesta V McNeill, Susan Cook
1Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle Upon Tyne, UK. i.r.logan@warwick.ac.uk
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.
