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


CONCLUSIONS
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.
Logan
Ian R
IR
Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle Upon Tyne, UK. i.r.logan@warwick.ac.uk
McNeill
Hesta V
HV
Cook
Susan
S
Lu
Xiaohong
X
Lunec
John
J
Robson
Craig N
CN
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018506:Gene Expression Regulation, Plant / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000097642:GADD45 Proteins
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D007093:Imidazoles; D009687:Nuclear Proteins; D010879:Piperazines; D017430:Prostate-Specific Antigen; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D011944:Receptors, Androgen; C438378:BBC3 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C482205:nutlin 3; C497206:MDM2 protein, human