LG Household & Health Care (LG H&H) R&D Center, 70, Magokjoongang 10-ro, Gangseo-gu, Seoul, 07795, Republic of Korea.
LG Household & Health Care (LG H&H) R&D Center, 70, Magokjoongang 10-ro, Gangseo-gu, Seoul, 07795, Republic of Korea.
Eur J Pharmacol. 2022 Feb 15;917:174743. doi: 10.1016/j.ejphar.2022.174743. Epub 2022 Jan 5.
The androgen receptor is a hormone activated transcription factor that regulates the development and maintenance of male characteristics and represents one of the most well-established drug targets, being implicated not only in prostate cancer but also in many non-cancerous human diseases including androgenetic alopecia, acne vulgaris, and hirsutism. In this study, the antiandrogenic effects of FMN were investigated in 22Rv1 and LNCaP prostate cancer cells. FMN inhibited dihydrotestosterone (DHT)-induced protein expression of androgen receptor in 22Rv1cells. In another prostate cancer LNCaP cells, FMN decreased the protein level of DHT-induced prostate specific antigen (PSA). In addition, FMN downregulated DHT-induced mRNA expression of androgen regulated genes in both cell lines, showing less prominent inhibition in 22Rv1cells where androgen receptor had been significantly decreased by FMN. FMN was found to bind androgen receptor, demonstrating that it acted as a competitive androgen receptor antagonist. FMN increased the phosphorylation of Akt in 22Rv1 cells and this increment was abrogated by PI3K inhibitor wortmannin, resulting in a rescued androgen receptor protein level which was decreased by FMN. Additionally, FMN was found to increase the mRNA and protein level of E3 ligase mouse double minute 2. Our data suggest that the androgen receptor signaling is regulated through PI3K-Akt-MDM2 pathway in 22Rv1 cells. Together, our results indicate that FMN facilitated the degradation of androgen receptor in 22Rv1 cells and inhibited the expression of androgen regulated genes by competing the binding of DHT to androgen receptor in LNCaP cells, demonstrating its therapeutic potential as an antiandrogen.
雄激素受体是一种激素激活的转录因子，调节男性特征的发育和维持，是最成熟的药物靶点之一，不仅与前列腺癌有关，而且与许多非癌性人类疾病有关，包括雄激素性脱发、寻常痤疮和多毛症。在这项研究中，研究了 FMN 在 22Rv1 和 LNCaP 前列腺癌细胞中的抗雄激素作用。FMN 抑制二氢睾酮（DHT）诱导的 22Rv1 细胞中雄激素受体的蛋白表达。在另一种前列腺癌细胞 LNCaP 中，FMN 降低了 DHT 诱导的前列腺特异性抗原（PSA）的蛋白水平。此外，FMN 下调了这两种细胞系中 DHT 诱导的雄激素调节基因的 mRNA 表达，在雄激素受体被 FMN 显著下调的 22Rv1 细胞中抑制作用不那么明显。发现 FMN 与雄激素受体结合，表明它作为一种竞争性雄激素受体拮抗剂起作用。FMN 增加了 22Rv1 细胞中 Akt 的磷酸化，而 PI3K 抑制剂wortmannin 则消除了这种增加，导致 FMN 降低的雄激素受体蛋白水平得到恢复。此外，还发现 FMN 增加了 E3 连接酶小鼠双微体 2 的 mRNA 和蛋白水平。我们的数据表明，在 22Rv1 细胞中，雄激素受体信号通过 PI3K-Akt-MDM2 途径进行调节。总之，我们的结果表明，FMN 通过促进雄激素受体在 22Rv1 细胞中的降解，并通过与 DHT 竞争结合雄激素受体来抑制 LNCaP 细胞中雄激素调节基因的表达，从而发挥其作为抗雄激素的治疗潜力。
