Chemopreventive effects of angiotensin II receptor type 2 agonist on prostate carcinogenesis by the down-regulation of the androgen receptor.
Chemopreventive effects of angiotensin II receptor type 2 agonist on prostate carcinogenesis by the down-regulation of the androgen receptor.
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DOI：
10.18632/oncotarget.24492
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发表时间：
2018-03-02
期刊：
影响因子：
--
通讯作者：
Uemura H
中科院分区：
文献类型：
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作者：
Ito Y;Naiki-Ito A;Kato H;Suzuki S;Kuno T;Ishiguro Y;Takahashi S;Uemura H
我们最近报道了血管紧张素II受体阻滞剂（ARBs）通过减少雄激素受体（AR）的表达，对前列腺癌具有化学预防和化学治疗的潜力。在这项研究中，我们利用我们实验室之前建立的前列腺腺癌转基因大鼠（TRAP）模型，研究了血管紧张素II受体2型（AT2R）激动剂化合物21 （C21）在前列腺癌发生中的作用，该化合物有望发挥与ARB相似的作用。使用LNCaP细胞进行细胞生长、Western blotting和报告基因检测的体外分析。6周龄的TRAP大鼠随机分为3组，每组12只，分别在饮水中给予C21 1或2 mg/kg/d，连续12周。C21降低前列腺癌细胞的增殖活性，下调PSA启动子活性和AR蛋白表达。我们发现C21可以抑制TRAP大鼠前列腺癌的进展，降低前列腺侧侧腺癌的发病率。免疫组化和Western blotting观察到caspase 3和caspase 7活化后细胞凋亡指数显著升高。C21还能显著下调TRAP大鼠前列腺中AR的表达。C21能有效降低前列腺癌细胞和TRAP大鼠前列腺中AR的表达，降低其增殖活性。这些发现提示AT2R激动剂可能是一种候选的新型化学预防人类前列腺癌的药物。
We recently reported that angiotensin II receptor blockers (ARBs) have chemopreventive and chemotherapeutic potential against prostate cancer via the reduction of androgen receptor (AR) expression. In this study, we investigated the effects of the angiotensin II receptor type 2 (AT2R) agonist Compound 21 (C21), which is expected to play similar roles to an ARB, on prostate carcinogenesis using the transgenic rat for adenocarcinoma of prostate (TRAP) model previously established in our laboratory. In vitro analyses of the cell growth, Western blotting and reporter gene assays were performed using LNCaP cells. TRAP rats at 6 weeks of age were randomly divided into 3 groups of 12 animals each and treated with C21 at 1 or 2 mg/kg/day in drinking water for 12 weeks. C21 reduced the proliferation activity of prostate cancer cells and down-regulated the PSA promoter activity and the AR protein expression. We discovered that C21 inhibited the progression of prostate carcinogenesis in TRAP rats and decreased the incidence of adenocarcinoma in the lateral prostate. A significant increase in the apoptotic index with activation of caspase 3 and 7 were observed by immunohistochemistry and Western blotting analyses. C21 also down-regulated the expression of AR significantly in TRAP rat prostate. C21 decreased the expression of AR and reduced the proliferation activity effectively in prostate cancer cells and TRAP rat prostate. These findings suggest that AT2R agonist may be a candidate novel chemopreventive agent against human prostate cancer.