Transforming growth factor-β1 induces nuclear to cytoplasmic distribution of androgen receptor and inhibits androgen response in prostate smooth muscle cells
Transforming growth factor-β1 induces nuclear to cytoplasmic distribution of androgen receptor and inhibits androgen response in prostate smooth muscle cells
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DOI：
10.1210/en.139.8.3569
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发表时间：
1998-08-01
期刊：
影响因子：
4.8
通讯作者：
Rowley, DR
中科院分区：
文献类型：
--
作者：
Gerdes, MJ;Dang, TD;Rowley, DR
前列腺中的基质-上皮相互作用依赖于前列腺基质细胞的雄激素调节，但对于雄激素在这些细胞类型中的作用知之甚少。最近的报告表明，某些生长因子可以刺激或抑制雄激素调节的基因转录，这表明了串扰机制。为了解决前列腺基质细胞中雄激素和转化生长因子-β 1 (TGF beta 1) 之间信号通路中潜在的串扰问题，对 PS-1 前列腺平滑肌细胞系进行了检查。在生理浓度的雄激素存在下，PS-1细胞增殖受到刺激，雄激素受体（AR）表现出核定位模式。添加 TGF beta 1 (25 pM) 能够阻断雄激素诱导的增殖，但在不含雄激素的培养物中没有直接作用。免疫细胞化学定位 AR 亚细胞分布表明，TGF beta 1 (5-100 par) 改变了 AR 从细胞核到细胞质的分布。其他生长因子，包括成纤维细胞生长因子-2、表皮生长因子和 TGF beta 2 对 AR 分布没有影响。 TGF β 1 诱导的受体定位从核到细胞质的变化很快（30 分钟内开始），被 TGF β 1 抗体中和，不需要新的蛋白质合成，并在 6 小时内完成。从培养基中去除 TGF beta 1 导致 AR 快速重新分布到细胞核，表明这是可逆机制。对 PS-1 细胞中雄激素作用的 ddp17 标记转录本的 Northern 分析表明，雄激素刺激的 ddp17 表达在 TGF beta 1 (25 pM) 存在的情况下受到抑制。在大鼠前列腺基质细胞的原代培养物中，TGF beta 1 诱导了类似的 AR 细胞核和细胞质分布。然而，TGF beta 1 对 LNCaP 前列腺癌细胞系或 DDT1MF-8 平滑肌肉瘤细胞系中的 AR 分布没有影响。前列腺基质细胞中TGFβ1和AR信号通路之间的特异性相互作用可能在前列腺发育和癌症进展中基质细胞反应中发挥重要作用。
Stromal-epithelial interactions in the prostate gland are dependent on androgen regulation of prostate stromal cells, yet little is known about androgen action in these cell types. Recent reports have demonstrated that androgen-regulated gene transcription can be stimulated or inhibited by certain growth factors, indicating crosstalk mechanisms. To address potential cross-talk in signaling pathways between androgen and transforming growth factor-beta 1 (TGF beta 1) in prostate stromal cells, the PS-1 prostate smooth muscle cell line was examined. In the presence of physiological concentrations of androgen, PS-1 cell proliferation was stimulated, and androgen receptor (AR) exhibited a nuclear localization pattern. The addition of TGF beta 1 (25 pM) was capable of blocking androgen-induced proliferation, but had no direct effect in cultures without androgen. Immunocytochemistry to localize AR subcellular distribution showed that TGF beta 1 (5-100 par) altered the distribution of AR from the nucleus to the cytoplasm. Other growth factors, including fibroblast growth factor-2, epidermal growth factor, and TGF beta 2 had no effect on AR distribution. The TGF beta 1-induced nuclear to cytoplasmic change in receptor localization was rapid (initiated within 30 min), was neutralized by TGF beta 1 antibodies, did not require new protein synthesis, and was complete by 6 h. Removal of TGF beta 1 from the culture medium resulted in a rapid redistribution of AR to the nucleus, indicating reversible mechanisms. Northern analysis of the ddp17 marker transcript for androgen action in PS-1 cells showed that androgen-stimulated ddp17 expression was inhibited in the presence of TGF beta 1 (25 pM). TGF beta 1 induced a similar nuclear to cytoplasmic distribution of AR in primary cultures of rat prostate stromal cells. TGF beta 1, however, had no effect on AR distribution in either the LNCaP prostatic carcinoma cell line or the DDT1MF-8 leiomyosacroma cell line. Specific cross-talk between TGF beta 1 and AR signaling pathways in prostate stromal cells may play a significant role in prostate development and stromal cell response in carcinoma progression.