Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer
Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer
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DOI：
10.1002/pros.22505
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发表时间：
2012-10-01
期刊：
影响因子：
2.8
通讯作者：
Shirai, Tomoyuki
中科院分区：
文献类型：
--
作者：
Takahashi, Satoru;Uemura, Hiroji;Shirai, Tomoyuki
背景随着抗去势前列腺癌(CRPC)的治疗策略有限，公众的兴趣集中在前列腺癌的潜在预防上。最近的研究表明，血管紧张素II受体阻滞剂(ARB)具有降低血清前列腺特异性抗原(PSA)水平和改善CRPC患者行为状态的潜力。这些事实促使我们调查ARB对前列腺癌生长和进展的直接影响。方法采用本实验室建立的转基因大鼠前列腺癌模型。3周龄TRAP大鼠在饮水中分别给予2或10 mg/kg/d的ARB(替米沙坦或坎地沙坦)灌胃12周。用LNCaP细胞进行体外细胞生长分析、泛素化或报告基因检测。结果替米沙坦和坎地沙坦均可抑制TRAP大鼠前列腺癌的发生，其机制可能与caspase激活、p38MAPK失活和雄激素受体(AR)下调导致的细胞凋亡有关。此外，基因芯片分析表明，ARB治疗上调了雌激素受体β(ERβ)的表达。在亲代和雄激素非依赖性LNCaP细胞中，ARB抑制细胞生长和AR介导的转录活性。ARB还通过上调ERβ对AR介导的转录激活起到轻微的附加作用。一项干预研究显示，与安慰剂对照组相比，接受ARB治疗的前列腺癌患者PSA进展时间延长。结论ARB可作为前列腺癌潜在的化学预防和化疗药物。前列腺癌72：15591572,2012年。(C)2012年威利期刊公司。
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 beta (ER beta) 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 ER beta up-regulation. An intervention study revealed that PSA progression was prolonged in prostate cancer patients given an ARB compared with placebo control. CONCLUSION These data provide a new concept that ARBs are promising potential chemopreventive and chemotherapeutic agents for prostate cancer. Prostate 72:15591572, 2012. (c) 2012 Wiley Periodicals, Inc.