Statins reduce the androgen sensitivity and cell proliferation by decreasing the androgen receptor protein in prostate cancer cells.
BACKGROUND
Statins (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors) are cholesterol-lowering drugs that are widely used to prevent and treat atherosclerotic cardiovascular disease. Recent epidemiological studies suggest that statins reduce serum prostate-specific antigen (PSA) levels and decrease the risk of prostate cancer. In the present study, we determined the molecular mechanisms related to the regulation of PSA, androgen receptor (AR) and cell proliferation in prostate cancer cell lines by statins.


METHODS
Western blotting, quantitative real-time polymerase chain reaction, cytotoxicity analysis and a cell proliferation assay were used to resolve the regulatory role of statins (mevastatin and simvastatin) in three prostate cancer cell lines, RWPE-1, 22Rv1, and LNCaP.


RESULTS
Western blotting revealed that both mevastatin and simvastatin downregulated AR and PSA protein. However, these statins did not downregulate AR mRNA expression, while they decreased PSA mRNA. The protease inhibitor MG132 inhibited the downregulation of AR protein which suggested that statins decreased AR protein levels by increasing AR proteolysis. Furthermore, statins reduced cell proliferation in AR positive cells but not in AR negative cells, suggesting that statins regulate cell proliferation via AR expression. In addition, cell proliferation assay at various concentrations of dihydrotestosterone (DHT) showed that statins decreased androgen sensitivity in LNCaP cells.


CONCLUSIONS
Statins decreased AR protein by proteolysis but not mRNA transcription. The drop in AR levels resulted in a reduction in androgen sensitivity and a decrease in cell proliferation in AR positive prostate cancer cells.
Yokomizo
Akira
A
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan. yokoa@uro.med.kyushu-u.ac.jp
Shiota
Masaki
M
Kashiwagi
Eiji
E
Kuroiwa
Kentaro
K
Tatsugami
Katsunori
K
Inokuchi
Junichi
J
Takeuchi
Ario
A
Naito
Seiji
S
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000502:physiology; D011944:Receptors, Androgen / Q000032:analysis* / Q000235:genetics
C410798:AR protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D017526:Receptor, IGF Type 1; D017430:Prostate-Specific Antigen; D046988:Proteasome Endopeptidase Complex