Xenoestrogen action in prostate cancer: pleiotropic effects dependent on androgen receptor status.
Xenoestrogen action in prostate cancer: pleiotropic effects dependent on androgen receptor status.
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DOI：
10.1158/0008-5472.54.65.1
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发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
Yelena B. Wetherill;Nicola L Fisher;Ann Staubach;M. Danielsen;R. de Vere White;K. Knudsen
中科院分区：
文献类型：
--
作者：
Yelena B. Wetherill;Nicola L Fisher;Ann Staubach;M. Danielsen;R. de Vere White;K. Knudsen
雄激素对前列腺的发育、生长和生存至关重要。晚期前列腺癌的治疗旨在阻断雄激素受体（AR）的作用。然而，复发肿瘤最终出现，其中含有恢复的AR活性。这种再激活的一种机制通过AR突变发生，使受体对非规范配体产生反应。我们之前已经证明，已知的异种雌激素双酚a （BPA）可以激活肿瘤来源的AR突变体（T877A），导致雄激素不依赖型前列腺癌细胞增殖。在这里，我们发现双酚a与雄激素合作激活AR-T877A，报告基因检测和前列腺特异性抗原表达水平的增加都表明了这一点。酵母和哺乳动物模型系统的进一步研究表明，多个AR等位基因对BPA有反应，从而扩大了异种雌激素对前列腺癌的潜在影响。此外，体外放射配体结合实验显示，BPA可能通过非竞争性抑制改变了5 α -二氢睾酮与AR-T877A的结合。我们还发现，高浓度BPA可阻断ar阳性、雄激素依赖性前列腺癌细胞（LNCaP和LAPC-4）的增殖，对雄激素非依赖性细胞的抑制作用较为温和（22Rv-1）。相比之下，ar阴性前列腺癌细胞在暴露于高剂量BPA后没有表现出生长抑制。总之，这些数据表明BPA可以作为晚期前列腺腺癌中突变ARs的潜在“激素增敏剂”，因此可能有助于晚期前列腺癌患者的治疗复发，并支持非甾体环境化合物可以改变核受体复合物功能的观点。
Androgen is critical for prostate development, growth, and survival. Therapies for advanced prostate cancer aim to block androgen receptor (AR) action. However, recurrent tumors ultimately arise, which harbor restored AR activity. One mechanism of such reactivation occurs through AR mutations, rendering the receptor responsive to noncanonical ligands. We have shown previously that a known xenoestrogen, bisphenol A (BPA), activates a tumor-derived AR mutant (T877A), leading to androgen-independent prostate cancer cell proliferation. Here, we show that BPA cooperates with androgen to activate AR-T877A as shown by both reporter assays and increased levels of prostate-specific antigen expression. Further investigations using both yeast and mammalian model systems revealed that multiple AR alleles are responsive to BPA, thus expanding the potential influence of xenoestrogens on prostate cancer. Moreover, in vitro radioligand binding assay revealed that BPA alters 5alpha-dihydrotestosterone binding to AR-T877A likely through noncompetitive inhibition. We also show that higher concentrations of BPA block proliferation of AR-positive, androgen-dependent prostate adenocarcinoma cells (LNCaP and LAPC-4), with a more modest inhibitory effect on androgen-independent cells (22Rv-1). By contrast, AR-negative prostate cancer cells failed to show growth inhibition after exposure to high BPA dose. Together, these data show that BPA can serve as a potential "hormone sensitizer" of the mutant ARs present in advanced prostate adenocarcinomas, thereby possibly contributing toward therapeutic relapse in advanced prostate cancer patients and supporting the notion that nonsteroidal environmental compounds can alter the function of nuclear receptor complexes.