Department of Urology, New York Medical College, Valhalla, NY 10595, USA.
Urol Oncol. 2013 Jan;31(1):104-9. doi: 10.1016/j.urolonc.2010.11.009. Epub 2011 Jul 27.
To investigate the effects of an antibiotic brefeldin A (BFA) on androgen-regulated cellular events in androgen-responsive prostate cancer cells, focusing on PSA (prostate-specific antigen) status, cell growth, and bioactivity of androgen receptor (AR).
Androgen-responsive human prostate cancer LNCaP cells were employed and 5α-dihydrotestosterone (DHT) was used as an androgenic mediator to induce androgen-modulated cellular events. Effects of BFA on synthesis and secretion of PSA, cell growth, and AR activity were assessed using Tandem PSA assay, trypan blue exclusion method, and AR binding assay, respectively.
BFA (30 ng/ml) dramatically (90%) blocked secretion of PSA and also reduced cell growth by >75% under non-androgen-regulated condition. Under androgen-stimulated condition using DHT (1 nM), both the cellular and secreted PSA levels as well as cell growth was significantly elevated or stimulated by DHT (compared with controls); however, BFA was capable of completely inhibiting such DHT-stimulated cellular events. In addition, AR binding assay revealed that AR activity has been drastically (~90%) diminished by BFA, likely resulting in interruption of DHT-mediated events.
BFA is capable of attenuating androgenic regulation in LNCaP cells such as androgen-stimulated PSA synthesis/secretion and cell growth. This BFA-blocked androgen action appears to be primarily attributed to severe inactivation of AR with BFA because AR is a crucial factor for relaying androgenic messages (to DNA). Therefore, BFA could be considered a promising agent for a more effective treatment of hormone-dependent prostate cancer.
研究抗生素布雷菲德菌素 A（BFA）对雄激素调节的前列腺癌细胞中细胞事件的影响，重点关注 PSA（前列腺特异性抗原）状态、细胞生长和雄激素受体（AR）的生物活性。
使用雄激素反应性人前列腺癌细胞 LNCaP，并使用 5α-二氢睾酮（DHT）作为雄激素介质诱导雄激素调节的细胞事件。使用 Tandem PSA 测定法、台盼蓝排斥法和 AR 结合测定法分别评估 BFA 对 PSA 的合成和分泌、细胞生长和 AR 活性的影响。
BFA（30ng/ml）在非雄激素调节条件下可显著阻断 PSA 的分泌，并使细胞生长减少>75%。在使用 DHT（1 nM）的雄激素刺激条件下，细胞和分泌的 PSA 水平以及细胞生长均被 DHT 显著升高或刺激（与对照相比）；然而，BFA 能够完全抑制这种 DHT 刺激的细胞事件。此外，AR 结合测定法显示，BFA 极大地降低了 AR 活性（约 90%），可能导致 DHT 介导的事件中断。
BFA 能够减弱 LNCaP 细胞中的雄激素调节，如雄激素刺激的 PSA 合成/分泌和细胞生长。这种 BFA 阻断雄激素作用主要归因于 BFA 对 AR 的严重失活，因为 AR 是传递雄激素信息（至 DNA）的关键因素。因此，BFA 可被视为治疗激素依赖性前列腺癌的更有效药物。
