Molecular Basis of Steroid Action in the Prostate.
Molecular Basis of Steroid Action in the Prostate.
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DOI：
10.1901/jaba.2005.1-27
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发表时间：
2005-04
期刊：
影响因子：
--
通讯作者：
Yuan-Shan Zhu
中科院分区：
文献类型：
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作者：
Yuan-Shan Zhu
雄激素通过雄激素受体(AR)发挥作用，在良性前列腺增生症(BPH)和前列腺癌的发生、发展中起重要作用。在过去的三十年里，人们进行了密集的研究，以阐明雄激素在前列腺中作用的分子基础。人们已经认识到，包括人类在内的哺乳动物体内存在两种天然的强效雄激素。虽然睾酮是睾丸分泌的主要雄激素，但双氢睾酮(DHT)是前列腺中的主要雄激素，通过AR介导雄激素的作用。到目前为止，只有一个AR被鉴定出来，它是类固醇/核受体超家族的成员，是一种配体依赖的核转录因子。当雄激素与AR结合时，这会导致AR内的构象变化，导致调节雄激素靶基因表达的辅助调节因子和转录因子的招募。前列腺癌中的雄激素作用也可以通过雌激素受体(ER)受到雌激素等其他激素的调节。已知的ER有两种亚型，ERα和ERβ，它们都与AR在前列腺和前列腺肿瘤细胞中共表达，这为AR和ER之间的直接相互作用提供了解剖学基础。虽然众所周知，雄激素对前列腺发育以及BPH和前列腺癌的发病机制都很重要，但雄激素如何控制这些过程的确切机制还不完全清楚。此外，前列腺或前列腺肿瘤细胞内的其他激素直接调节雄激素受体作用的证据正在出现，这些激素的临床意义正在探索中。在这篇文章中，我们将评估雄激素，尤其是DHT在前列腺生理学以及在BPH和前列腺癌发病机制中的重要性。我们还将回顾AR和ER及其各自的配体在前列腺细胞中相互作用的分子性质，以及它们潜在的临床意义。
Androgens acting via androgen receptor (AR) play essential roles in the prostate development, growth and pathogenesis of benign prostate hyperplasia (BPH) and prostate cancer. Over the last three decades, intensive studies have been carried out to elucidate the molecular basis of androgen action in the prostate. It has been realized that there are two natural potent androgens in the mammal including humans. Although testosterone is the major androgen secreted from the testes, dihydrotestosterone (DHT) is the main androgen in the prostate to mediate the androgen action via the AR. Only one AR has been identified up to date, a member of the steroid/nuclear receptor superfamily, which is a ligand-dependent nuclear transcription factor. When androgens bind to the AR, this results in a conformational change within the AR, leading to the recruitment of co-regulators and transcription factors which mediate androgen-target gene expression. Androgen actions in the prostate can also be modulated by other hormones such as estrogens via estrogen receptors (ER). There are two known isoforms of the ER, ERα and ERβ, which are both co-expressed with AR in the prostate and prostate tumor cells, which provides an anatomical basis for a direct interplay between AR and ER. Although it is well known that androgens are important for prostate development and for the pathogenesis of BPH and prostate cancer, the precise mechanisms as to how androgens control these processes are not yet fully understood. Furthermore, evidence for the direct modulation of androgenAR actions by other hormones within the prostate or prostate tumor cells is emerging, and the clinical implications of these hormones is being explored. In this article, we will assess the importance of androgens, and especially DHT, in prostate physiology and in the pathogenesis of BPH and prostate cancer. We will also review the molecular nature of the interactions between AR and ER and their respective ligands in prostate cells, as well their potential clinical implications.