Kang H Y, Lin H K, Hu Y C, Yeh S, Huang K E, Chang C
George Whipple Laboratory for Cancer Research, Department of Pathology, of Rochester Medical Center, Rochester, NY 14642, USA.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3018-23. doi: 10.1073/pnas.061305498. Epub 2001 Mar 6.
Although transforming growth factor-beta (TGF-beta) has been identified to mainly inhibit cell growth, the correlation of elevated TGF-beta with increasing serum prostate-specific antigen (PSA) levels in metastatic stages of prostate cancer has also been well documented. The molecular mechanism for these two contrasting effects of TGF-beta, however, remains unclear. Here we report that Smad3, a downstream mediator of the TGF-beta signaling pathway, functions as a coregulator to enhance androgen receptor (AR)-mediated transactivation. Compared with the wild-type AR, Smad3 acts as a strong coregulator in the presence of 1 nM 5alpha-dihydrotestosterone, 10 nM 17beta-estradiol, or 1 microM hydroxyflutamide for the LNCaP mutant AR (mtAR T877A), found in many prostate tumor patients. We further showed that endogenous PSA expression in LNCaP cells can be induced by 5alpha-dihydrotestosterone, and the addition of the Smad3 further induces PSA expression. Together, our findings establish Smad3 as an important coregulator for the androgen-signaling pathway and provide a possible explanation for the positive role of TGF-beta in androgen-promoted prostate cancer growth.
尽管已确定转化生长因子-β（TGF-β）主要抑制细胞生长，但在前列腺癌转移阶段，TGF-β升高与血清前列腺特异性抗原（PSA）水平升高之间的相关性也有充分记录。然而，TGF-β这两种相反作用的分子机制仍不清楚。在此我们报告，TGF-β信号通路的下游介质Smad3作为一种共调节因子，增强雄激素受体（AR）介导的反式激活。与野生型AR相比，在许多前列腺肿瘤患者中发现的LNCaP突变体AR（mtAR T877A）在存在1 nM 5α-二氢睾酮、10 nM 17β-雌二醇或1 μM氟他胺的情况下，Smad3作为一种强大的共调节因子发挥作用。我们进一步表明，LNCaP细胞中的内源性PSA表达可被5α-二氢睾酮诱导，添加Smad3可进一步诱导PSA表达。总之，我们的研究结果确立了Smad3作为雄激素信号通路的重要共调节因子，并为TGF-β在雄激素促进的前列腺癌生长中的积极作用提供了一种可能的解释。
