title: Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  These data provide a new concept that ARBs are promising potential chemopreventive and chemotherapeutic agents for prostate cancer.
authors.affiliation: Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. sattak@med.nagoya-cu.ac.jp
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hiroji
authors.initials: H
authors.lastname: Uemura
authors.forename: Azman
authors.initials: A
authors.lastname: Seeni
authors.forename: Mingxi
authors.initials: M
authors.lastname: Tang
authors.forename: Masami
authors.initials: M
authors.lastname: Komiya
authors.forename: Ne
authors.initials: N
authors.lastname: Long
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishiguro
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kubota
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D047629:Estrogen Receptor beta; D011944:Receptors, Androgen; D013777:Tetrazoles; C081643:candesartan; D000077333:Telmisartan