Yang Qing, Titus Mark A, Fung Kar-Ming, Lin Hsueh-Kung
Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
J Cell Biochem. 2008 Aug 1;104(5):1612-24. doi: 10.1002/jcb.21731.
Androgen and androgen receptor (AR) are involved in growth of normal prostate and development of prostatic diseases including prostate cancer. Androgen deprivation therapy is used for treating advanced prostate cancer. This therapeutic approach focuses on suppressing the accumulation of potent androgens, testosterone and 5alpha-dihydrotestosterone (5alpha-DHT), or inactivating the AR. Unfortunately, the majority of patients with prostate cancer eventually advance to androgen-independent states and no longer respond to the therapy. In addition to the potent androgens, 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), reduced from 5alpha-DHT through 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs), activated signaling may represent a novel pathway responsible for the progression to androgen-independent prostate cancer. Androgen sensitive human prostate cancer LNCaP cells were used to compare 5alpha-DHT and 3alpha-diol activated androgenic effects. In contrast to 5alpha-DHT, 3alpha-diol regulated unique patterns of beta-catenin and Akt expression as well as Akt phosphorylation in parental and in AR-silenced LNCaP cells. More significantly, 3alpha-diol, but not 5alpha-DHT, supported AR-silenced LNCaP cells and AR negative prostate cancer PC-3 cell proliferation. 3alpha-diol-activated androgenic effects in prostate cells cannot be attributed to the accumulation of 5alpha-DHT, since 5alpha-DHT formation was not detected following 3alpha-diol administration. Potential accumulation of 3alpha-diol, as a result of elevated 3alpha-HSD expression in cancerous prostate, may continue to support prostate cancer growth in the presence of androgen deprivation. Future therapeutic strategies for treating advanced prostate cancer might need to target reductive 3alpha-HSD to block intraprostatic 3alpha-diol accumulation.
雄激素和雄激素受体（AR）参与正常前列腺的生长以及包括前列腺癌在内的前列腺疾病的发展。雄激素剥夺疗法用于治疗晚期前列腺癌。这种治疗方法侧重于抑制强效雄激素睾酮和5α-二氢睾酮（5α-DHT）的积累，或使AR失活。不幸的是，大多数前列腺癌患者最终会发展为雄激素非依赖状态，不再对该疗法产生反应。除了强效雄激素外，由5α-DHT通过3α-羟基类固醇脱氢酶（3α-HSDs）还原生成的5α-雄甾烷-3α,17β-二醇（3α-二醇）激活的信号传导可能代表了一条导致进展为雄激素非依赖型前列腺癌的新途径。利用雄激素敏感的人前列腺癌LNCaP细胞比较5α-DHT和3α-二醇激活的雄激素效应。与5α-DHT不同，3α-二醇在亲本和AR沉默的LNCaP细胞中调节β-连环蛋白和Akt表达以及Akt磷酸化的独特模式。更重要的是，3α-二醇而非5α-DHT支持AR沉默的LNCaP细胞和AR阴性前列腺癌PC-3细胞的增殖。3α-二醇在前列腺细胞中激活的雄激素效应不能归因于5α-DHT的积累，因为在给予3α-二醇后未检测到5α-DHT的形成。由于癌性前列腺中3α-HSD表达升高导致的3α-二醇潜在积累，可能在雄激素剥夺的情况下继续支持前列腺癌的生长。未来治疗晚期前列腺癌的策略可能需要靶向还原型3α-HSD以阻断前列腺内3α-二醇的积累。
