The role of the androgen receptor in the development of prostatic hyperplasia and prostate cancer
The role of the androgen receptor in the development of prostatic hyperplasia and prostate cancer
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DOI：
10.1023/a:1026057402945
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发表时间：
2003-11-01
影响因子：
4.3
通讯作者：
Chatterjee, B
中科院分区：
文献类型：
--
作者：
Chatterjee, B
雄激素受体（AR）是一种雄激素诱导的转录因子，其特征在于模块化的一级结构，每个模块代表一个不同的功能单元。在其与雄激素相互作用后，胞质AR被激活并易位至细胞核，在细胞核中其在雄激素应答元件处结合至靶基因，并募集共调节因子以形成多蛋白复合物，该多蛋白复合物与转录介质和基础转录机制相互作用以调节基因转录。雄激素在正常前列腺的形态发生和生理学中起重要作用。良性前列腺增生（BPH）和前列腺肿瘤（可进展为腺癌）的病因是雄激素依赖性的，前列腺中雄激素作用的减少/消除已成为BPH和前列腺癌的首选治疗方法。在雄激素撤除和抗雄激素治疗后，雄激素响应性前列腺癌细胞停止增殖并经历凋亡，导致肿瘤消退。然而，当肿瘤表现为雄激素非依赖性和雄激素抵抗性时，复发总是可见的。AR中的基因扩增和氨基酸取代在复发性肿瘤中以高频率检测到。由于AR对低去势水平雄激素的超敏反应或受体构象的重新排列，这些变化赋予肿瘤细胞生长优势，导致配体特异性改变，使抗雄激素、肾上腺雄激素和非雄激素类固醇激动性地增加AR活性。野生型AR在治疗抗性肿瘤中的信号传导的持续性是由于AR与多个细胞内信号传导级联的串扰引起的受体活性增加，特别是生长因子激活的MAP激酶/ERK和PI 3激酶/Akt途径。使用反义寡脱氧核苷酸、核酶或小干扰RNA（RNAi）消融AR功能有望成为未来成功治疗难治性前列腺肿瘤的方法。
The androgen receptor (AR) is an androgen-inducible transcription factor characterized by a modular primary structure, with each module representing a distinct functional unit. After its interaction with androgens, the cytoplasmic AR is activated and translocated to the nucleus where it binds to target genes at the androgen responsive element(s) and recruits coregulators to form a multiprotein complex that interacts with transcriptional mediators and the basal transcription machinery to regulate gene transcription. Androgens play an essential role in the morphogenesis and physiology of the normal prostate. The etiology of benign prostatic hyperplasia (BPH) and prostatic neoplasia, which can progress to adenocarcinoma, is androgen-dependent, and reduction/obliteration of androgen action in the prostate has been the therapy of choice for BPH and prostate cancer. After androgen withdrawal and antiandrogen treatment, the androgen responsive prostate cancer cells cease to proliferate and undergo apoptosis, causing tumor regression. However, relapses are seen invariably, when tumors emerge as androgen-independent and apoptosis-resistant. Gene amplification and amino acid substitutions in the AR are detected at a high frequency in recurrent tumors. These changes confer growth advantage to the tumor cells due to either hypersensitivity of AR to low, castrate-level androgens or a realignment of the receptor conformation, leading to altered ligand specificity that enables antiandrogens, adrenal androgens and non-androgen steroids act agonistically to increase AR activity. Persistence of signaling by the wildtype AR in therapy-resistant tumors is due to the increased receptor activity caused by cross talk of AR with multiple intracellular signaling cascades, especially the growth factor activated MAP kinase/ERK and PI3 kinase/Akt pathways. Ablation of AR function using antisense oligodeoxynucleotides, ribozymes or small interference RNAs (RNAi) holds promise as future approaches to the successful treatment of hormone-refractory, apoptosis-resistant prostate tumors.