Verras Meletios, Sun Zijie
Department of Urology, R135, Edwards Building, Stanford University School of Medicine, Stanford, California 94305-5328, USA.
Mol Endocrinol. 2005 Feb;19(2):391-8. doi: 10.1210/me.2004-0208. Epub 2004 Oct 28.
The androgen-signaling pathway is important for the growth and progression of prostate cancer cells. IGF-I and other polypeptide growth factors have been shown to be capable of induction of androgen receptor (AR) activation in the absence of, or at low levels of, ligand. It has been shown that IGF-I increases the cellular level of beta-catenin, an AR coactivator. In this study, we performed several experiments to test whether beta-catenin is involved in IGF-I-induced AR-mediated transcription. We demonstrate that IGF-I enhances the expression of endogenous prostate-specific antigen, an AR target gene, and elevates the level of cytoplasmic and nuclear beta-catenin in prostate cancer cells. Transfection of either wild-type or a constitutively active mutant of the IGF-I receptor augments AR-mediated transcription. An antisense construct of beta-catenin that decreases the cellular level of beta-catenin can reduce IGF-1 receptor-mediated enhancement of AR activity. Moreover, using a pulse-chase experiment, we showed that IGF-I enhances the stability of beta-catenin in prostate cancer cells. Our findings delineate a novel pathway for IGF-I in modulating androgen signaling through beta-catenin.
雄激素信号通路对前列腺癌细胞的生长和进展至关重要。胰岛素样生长因子-I（IGF-I）和其他多肽生长因子已被证明在无配体或低水平配体的情况下能够诱导雄激素受体（AR）激活。研究表明，IGF-I可增加AR共激活因子β-连环蛋白的细胞水平。在本研究中，我们进行了多项实验，以测试β-连环蛋白是否参与IGF-I诱导的AR介导的转录。我们证明，IGF-I可增强内源性前列腺特异性抗原（一种AR靶基因）的表达，并提高前列腺癌细胞中细胞质和细胞核β-连环蛋白的水平。转染野生型或IGF-I受体的组成型活性突变体可增强AR介导的转录。一种可降低细胞β-连环蛋白水平的β-连环蛋白反义构建体可降低IGF-1受体介导的AR活性增强。此外，通过脉冲追踪实验，我们表明IGF-I可增强前列腺癌细胞中β-连环蛋白的稳定性。我们的研究结果描绘了一条IGF-I通过β-连环蛋白调节雄激素信号的新途径。
