Department of Movement, Human and Health Sciences, "Foro Italico" University, 00135 Rome, Italy.
Department of Experimental Medicine, "Sapienza" University of Rome, 00161 Rome, Italy.
Int J Mol Sci. 2021 Jan 13;22(2):754. doi: 10.3390/ijms22020754.
The androgen receptor (AR) plays a key role in normal prostate homeostasis and in prostate cancer (PCa) development, while the role of aromatase (Cyp19a1) is still unclear. We evaluated the effects of a treatment with Tadalafil (TAD) on both these proteins.
Androgen-sensitive human PCa cell line (LnCAP) was incubated with/without TAD (10 M) and bicalutamide (BCT) (10 M) to evaluate a potential modulation on cell proliferation, protein and mRNA expression of Cyp19a, AR and estrogen receptor-β (ERβ), respectively.
TAD increased early AR nuclear translocation ( < 0.05, after 15 min of exposure), and increased AR transcriptional activity ( < 0.05) and protein expression ( < 0.05) after 24 h. Moreover, after 24 h this treatment upregulated Cyp19a1 and ERβ mRNA ( < 0.05 and < 0.005 respectively) and led to an increase in protein expression of both after 48 h ( < 0.05). Interestingly, TAD counteracted Cyp19a1 stimulation induced by BCT ( < 0.05) but did not alter the effect induced by BCT on the AR protein expression.
We demonstrate for the first time that TAD can significantly modulate AR expression and activity, Cyp19a1 and ERβ expression in PCa cells, suggesting a specific effect of these proteins. In addition, TAD potentiates the antiproliferative activity of BCT, opening a new clinical scenario in the treatment of PCa.
雄激素受体 (AR) 在前列腺的正常稳态和前列腺癌 (PCa) 发展中起着关键作用，而芳香酶 (Cyp19a1) 的作用仍不清楚。我们评估了他达拉非 (TAD) 治疗对这两种蛋白的影响。
用/不用 TAD（10 μM）和比卡鲁胺（BCT）（10 μM）孵育雄激素敏感的人 PCa 细胞系 (LnCAP)，分别评估对细胞增殖、Cyp19a、AR 和雌激素受体-β (ERβ) 的蛋白和 mRNA 表达的潜在调节作用。
TAD 增加了早期 AR 核易位（<0.05，暴露 15 分钟后），并增加了 AR 转录活性（<0.05）和蛋白表达（<0.05）在 24 小时后。此外，经过 24 小时的治疗，该治疗上调了 Cyp19a1 和 ERβ 的 mRNA（<0.05 和 <0.005），并在 48 小时后导致两者的蛋白表达增加（<0.05）。有趣的是，TAD 拮抗了 BCT 诱导的 Cyp19a1 刺激（<0.05），但没有改变 BCT 对 AR 蛋白表达的影响。
我们首次证明 TAD 可以显著调节 AR 表达和活性、PCa 细胞中 Cyp19a1 和 ERβ 的表达，提示这些蛋白具有特定的作用。此外，TAD 增强了 BCT 的抗增殖活性，为治疗 PCa 开辟了新的临床前景。
