Androgen receptor coactivators and prostate cancer
Androgen receptor coactivators and prostate cancer
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DOI：
10.1007/978-0-387-69080-3_23
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发表时间：
2008-01-01
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影响因子：
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通讯作者：
Weigel, Nancy L.
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文献类型：
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作者：
Agoulnik, Irina U.;Weigel, Nancy L.
在美国男性中，前列腺癌(PC)是癌症死亡的第二大常见原因。因此，该病的病因、预防和治疗是一个主要的健康问题。前列腺的发育和分化依赖于雄激素，前列腺癌也依赖于雄激素(1)。因此，某种形式的雄激素剥夺是转移性前列腺癌的主要治疗方法。虽然最初在减轻肿瘤负担方面有效，但肿瘤对雄激素剥夺产生抵抗力，并在相对较短的时间内复发。雄激素的作用是由雄激素受体(AR)介导的，AR是一种激素激活的转录因子，属于配体激活的转录因子(2，3)大核受体超家族。AR与许多其他受体的不同之处在于它有两个天然的内源性配体。睾酮(T)(图1)是主要的循环雄激素，也是大多数组织中的主要激素。T在睾丸中产生，并在前列腺和选定的其他组织(包括皮肤)中通过5α还原酶转化为5α-双氢睾酮(图1)。DHT是一种亲和力较高的配体，在功能上是前列腺中最重要的雄激素。此外，还有许多雄激素代谢产物，包括DHEA和雄烯二醇，它们对AR的亲和力要低得多。虽然这些雄激素被认为在雄激素补充的男性的AR活动中不起主要作用，但当T和DHT水平因雄激素治疗而降低时，它们可能激活AR。尽管雄激素治疗失败的频率表明前列腺癌已经发展出在没有正常的雄激素循环水平的情况下生长的手段，但有很好的证据表明，这些肿瘤中的许多仍然依赖AR。事实上，治疗失败通常是由于血清PSA(前列腺特异性抗原)水平升高所致，PSA(前列腺特异性抗原)是一种在正常前列腺和前列腺癌中表达的雄激素调节的蛋白酶。这使得人们有兴趣了解AR是如何发挥作用的，并确定在雄激素水平降低的情况下，AR仍能发挥作用的变化。
Among USA men, prostate cancer (PC) is the second most common cause of death from cancer. Thus, the etiology, prevention, and treatment of the disease are a major health concern. Development and differentiation of the prostate is androgen dependent and PC, too, is androgen dependent (1). Consequently, some form of androgen deprivation is the primary treatment for metastatic PC. Although effective initially in reducing tumor burden, the tumors become resistant to androgen deprivation and recur within a relatively short period of time. The actions of androgens are mediated by the androgen receptor (AR) a hormone-activated transcription factor, which belongs to the large nuclear receptor superfamily of ligand-activated transcription factors (2, 3). AR differs from many of the other receptors in that it has two natural endogenous ligands. Testosterone (T)(Fig. 1) is the major circulating androgen and is the major hormone in most tissues. T is produced in the testis and is converted to 5α-dihydrotestosterone (DHT)(Fig. 1) by the enzyme 5αreductase in the prostate as well as in selected other tissues including skin. DHT is a higher affinity ligand and is functionally the most important androgen in the prostate. In addition, there are a number of androgen metabolites including DHEA and androstenediol, which have much lower affinities for AR. Although these androgens are not thought to play a major role in AR action in androgen-repleted males, they may activate the AR when levels of T and DHT are reduced as a result of androgen ablation therapy.Despite the frequency of failure of androgen ablation therapy indicating that the prostate tumors have developed means to grow without normal circulating levels of androgens, there is good evidence that many of these tumors remain dependent upon AR. Indeed, treatment failure is often detected due to increasing serum levels of PSA (prostate-specific antigen), an androgen-regulated protease expressed in normal prostate and in PC. This has led to interest in understanding how AR functions and in identifying the changes that permit AR to function despite reduced levels of androgens.