Zhao X Y, Malloy P J, Krishnan A V, Swami S, Navone N M, Peehl D M, Feldman D
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Nat Med. 2000 Jun;6(6):703-6. doi: 10.1038/76287.
The androgen receptor (AR) is involved in the development, growth and progression of prostate cancer (CaP). CaP often progresses from an androgen-dependent to an androgen-independent tumor, making androgen ablation therapy ineffective. However, the mechanisms for the development of androgen-independent CaP are unclear. More than 80% of clinically androgen-independent prostate tumors show high levels of AR expression. In some CaPs, AR levels are increased because of gene amplification and/or overexpression, whereas in others, the AR is mutated. Nonetheless, the involvement of the AR in the transition of CaP to androgen-independent growth and the subsequent failure of endocrine therapy are not fully understood. Here we show that in CaP cells from a patient who failed androgen ablation therapy, a doubly mutated AR functioned as a high-affinity cortisol/cortisone receptor (ARccr). Cortisol, the main circulating glucocorticoid, and its metabolite, cortisone, both equally stimulate the growth of these CaP cells and increase the secretion of prostate-specific antigen in the absence of androgens. The physiological concentrations of free cortisol and total cortisone in men greatly exceed the binding affinity of the ARccr and would activate the receptor, promoting CaP cell proliferation. Our data demonstrate a previously unknown mechanism for the androgen-independent growth of advanced CaP. Understanding this mechanism and recognizing the presence of glucocorticoid-responsive AR mutants are important for the development of new forms of therapy for the treatment of this subset of CaP.
雄激素受体（AR）参与前列腺癌（CaP）的发生、发展和进展。CaP通常会从雄激素依赖型肿瘤发展为雄激素非依赖型肿瘤，导致雄激素剥夺疗法失效。然而，雄激素非依赖型CaP的发生机制尚不清楚。超过80%的临床雄激素非依赖型前列腺肿瘤显示出高水平的AR表达。在一些CaP中，AR水平因基因扩增和/或过表达而升高，而在另一些CaP中，AR发生了突变。尽管如此，AR在CaP向雄激素非依赖型生长转变以及随后内分泌治疗失败中的作用尚未完全明确。在此我们表明，在一名雄激素剥夺治疗失败患者的CaP细胞中，一种双重突变的AR发挥了高亲和力皮质醇/可的松受体（ARccr）的作用。皮质醇是主要的循环糖皮质激素，其代谢产物可的松，在无雄激素的情况下均能同等程度地刺激这些CaP细胞的生长并增加前列腺特异性抗原的分泌。男性体内游离皮质醇和总可的松的生理浓度大大超过ARccr的结合亲和力，会激活该受体，促进CaP细胞增殖。我们的数据揭示了晚期CaP雄激素非依赖型生长的一种前所未知的机制。了解这一机制并认识到糖皮质激素反应性AR突变体的存在对于开发针对这一亚型CaP的新型治疗方法具有重要意义。
