Statins reduce the androgen sensitivity and cell proliferation by decreasing the androgen receptor protein in prostate cancer cells

Akira Yokomizo, masaki shiota, Eiji Kashiwagi, Kentaro Kuroiwa, Katsunori Tatsugami, Junichi Inokuchi, ario takeuchi, Seiji Naito

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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. Prostate 71:298-304, 2011. © 2010 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)298-304
Number of pages7
JournalProstate
Volume71
Issue number3
DOIs
Publication statusPublished - Feb 15 2011

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Androgen Receptors
Androgens
Simvastatin
Prostatic Neoplasms
Cell Proliferation
Proteins
Prostate-Specific Antigen
Down-Regulation
Messenger RNA
Proteolysis
Western Blotting
Anticholesteremic Agents
mevastatin
Cell Line
Antigen Receptors
Dihydrotestosterone
Protease Inhibitors
Real-Time Polymerase Chain Reaction
Epidemiologic Studies

All Science Journal Classification (ASJC) codes

  • Urology
  • Oncology

Cite this

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title = "Statins reduce the androgen sensitivity and cell proliferation by decreasing the androgen receptor protein in prostate cancer cells",
abstract = "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. Prostate 71:298-304, 2011. {\circledC} 2010 Wiley-Liss, Inc.",
author = "Akira Yokomizo and masaki shiota and Eiji Kashiwagi and Kentaro Kuroiwa and Katsunori Tatsugami and Junichi Inokuchi and ario takeuchi and Seiji Naito",
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TY - JOUR

T1 - Statins reduce the androgen sensitivity and cell proliferation by decreasing the androgen receptor protein in prostate cancer cells

AU - Yokomizo, Akira

AU - shiota, masaki

AU - Kashiwagi, Eiji

AU - Kuroiwa, Kentaro

AU - Tatsugami, Katsunori

AU - Inokuchi, Junichi

AU - takeuchi, ario

AU - Naito, Seiji

PY - 2011/2/15

Y1 - 2011/2/15

N2 - 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. Prostate 71:298-304, 2011. © 2010 Wiley-Liss, Inc.

AB - 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. Prostate 71:298-304, 2011. © 2010 Wiley-Liss, Inc.

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DO - 10.1002/pros.21243

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