S. Takahashi and H. Uemura contributed equally to this work.
Article first published online: 16 MAR 2012
Copyright © 2012 Wiley Periodicals, Inc.
Volume 72, Issue 14, pages 1559–1572, 1 October 2012
How to Cite
Takahashi, S., Uemura, H., Seeni, A., Tang, M., Komiya, M., Long, N., Ishiguro, H., Kubota, Y. and Shirai, T. (2012), Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer. Prostate, 72: 1559–1572. doi: 10.1002/pros.22505
Conflict of Interest: None.
- Issue published online: 24 AUG 2012
- Article first published online: 16 MAR 2012
- Manuscript Accepted: 15 FEB 2012
- Manuscript Received: 28 SEP 2011
- Ministry of Health, Labour and Welfare of Japan
- Society for Promotion of Pathology of Nagoya, Japan
- Ministry of Education, Culture, Science and Technology of Japan
- Umehara Foundation of Yokohama Medical Group
- angiotensin II receptor type 1;
- prostate cancer;
- androgen receptor;
- transgenic rat;
- intervention study
With the limited strategies for curative treatment of castration-resistant prostate cancer (CRPC), public interest has focused on the potential prevention of prostate cancer. Recent studies have demonstrated that an angiotensin II receptor blocker (ARB) has the potential to decrease serum prostate-specific antigen (PSA) level and improve performance status in CRPC patients. These facts prompted us to investigate the direct effects of ARBs on prostate cancer growth and progression.
Transgenic rat for adenocarcinoma of prostate (TRAP) model established in our laboratory was used. TRAP rats of 3 weeks of age received ARB (telmisartan or candesartan) at the concentration of 2 or 10 mg/kg/day in drinking water for 12 weeks. In vitro analyses for cell growth, ubiquitylation or reporter gene assay were performed using LNCaP cells.
We found that both telmisartan and candesartan attenuated prostate carcinogenesis in TRAP rats by augmentation of apoptosis resulting from activation of caspases, inactivation of p38 MAPK and down-regulation of the androgen receptor (AR). Further, microarray analysis demonstrated up-regulation of estrogen receptor β (ERβ) by ARB treatment. In both parental and androgen-independent LNCaP cells, ARB inhibited both cell growth and AR-mediated transcriptional activity. ARB also exerted a mild additional effect on AR-mediated transcriptional activation by the ERβ up-regulation. An intervention study revealed that PSA progression was prolonged in prostate cancer patients given an ARB compared with placebo control.
These data provide a new concept that ARBs are promising potential chemopreventive and chemotherapeutic agents for prostate cancer. Prostate 72:1559–1572, 2012. © 2012 Wiley Periodicals, Inc.