Androgen receptor regulation by physiological concentrations of the isoflavonoid genistein in androgen-dependent LNCaP cells is mediated by estrogen receptor β
Androgen receptor regulation by physiological concentrations of the isoflavonoid genistein in androgen-dependent LNCaP cells is mediated by estrogen receptor β
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DOI：
10.1016/j.eururo.2003.09.001
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发表时间：
2004-02-01
期刊：
影响因子：
23.4
通讯作者：
Klocker, H
中科院分区：
文献类型：
--
作者：
Bektic, J;Berger, AP;Klocker, H
目的：讨论异黄酮类化合物在前列腺癌化学预防和治疗中的应用。我们研究了金雀异黄素在人雄激素敏感的前列腺癌细胞系 LNCaP 中调节雄激素受体 (AR) 表达和转录活性的潜力。材料和方法：分别通过实时 RT-PCR 和免疫印迹分析 mRNA 和蛋白质水平的 AR 表达。在条件培养基中通过微粒酶免疫测定法(MEIA)测量PSA。在放射性配体结合测定中测试了金雀异黄酮与 AR 的结合，并采用报告基因共转染测定来研究 AR 活性。结果：使用在常规大豆饮食的亚洲男性血清中检测到的金雀异黄酮浓度，我们发现雄激素受体在 mRNA 和蛋白质水平上均下调。与甲基三烯醇 (R1881) 相比，与 AR 的相对结合亲和力低于 4%，并且浓度高达 1 μM 的金雀异黄素对 AR 转录活性没有调节作用。我们还证明了金雀异黄素治疗后 PSA 分泌受到抑制。由于抗雌激素ICI 164 384消除了金雀异黄素和ER-β的抑制作用，但LNCaP细胞中不表达ER-α，我们推测金雀异黄素对雄激素受体的作用机制是通过ER-P介导的。结论：使用金雀异黄素的生理浓度，我们发现金雀异黄素在前列腺癌细胞中通过ER-P下调AR。这可能会导致对激素刺激的反应发生改变，并可能有助于解释亚洲人群前列腺癌发病率较低的原因。 (C) 2003 Elsevier B.V. 保留所有权利。
Objectives: Isoflavonoids are discussed for use in chemoprevention and treatment of prostate cancer. We investigated the potential of genistein to modulate androgen receptor (AR) expression and transcriptional activity in the human androgen-sensitive prostate cancer cell line LNCaP.Materials and Methods: AR expression at mRNA and protein level was analyzed by real-time RT-PCR and immunoblot, respectively. In conditioned media PSA was measured by a microparticle enzyme immunoassay (MEIA). Binding of genistein to the AR was tested in a radioligand-binding assay and reporter gene co-transfection assay was employed to investigate AR activity.Results: Using concentrations of genistein that have been detected in sera of Asian men on regular soy-diet we found down-regulation of androgen receptor at both mRNA and protein level. The relative binding affinity to the AR was below 4% when compared to methyltrienologe (R1881) and there was no modulation of AR transcriptional activity by genistein concentrations up to 1 muM. We also demonstrated inhibition of PSA secretion after genistein treatment. As the anti-estrogen ICI 164 384 abolished the inhibitory effect of genistein and ER-beta, but not ER-alpha is expressed in LNCaP cells we postulate that the mechanism of genistein action on androgen receptor is mediated through ER-P.Conclusion: Using physiological concentrations of genistein we showed AR down-regulation by genistein in prostate cancer cells occurring via ER-P. This likely results in a modified response to hormonal stimuli and may help to explain the low incidence of prostate cancer in the Asian population. (C) 2003 Elsevier B.V. All rights reserved.