- 作者: Srinivas Rajamahanty; Catherine Alonzo; Shahrad Aynehchi; Muhammad Choudhury; Sensuke Konno
- 作者服務機構: Department of Urology, New York Medical College, Valhalla, NY, USA
- 中文摘要: --
- 英文摘要:
Background: Androgen ablation is one of the viable therapeutic options for patients
with primary hormone (androgen)-dependent prostate cancer. However, an antibiotic
brefeldin A (BFA) has been shown to exhibit the growth inhibitory effect on human
cancer cells. We thus investigated if BFA might inhibit proliferation of androgenresponsive
prostate cancer LNCaP cells and also explored how it would be carried out,
focusing on cell cycle and androgen receptor (AR).
Methods: Androgen-mediated cellular events in LNCaP cells were induced using 5α-
dihydrotestosterone (DHT) as an androgenic mediator. Effects of BFA on non-DHTstimulated
or DHT-stimulated cell growth were assessed. Its growth inhibitory
mechanism(s) was further explored; performing cell cycle analysis on a flow cytometer,
assessing AR activity by AR binding assay, and analyzing AR protein expression using
Western blot analysis.
Results: DHT (1 nM) was capable of stimulating LNCaP cell growth by ~40% greater
than non-stimulated controls, whereas BFA (30 ng/ml) completely inhibited such DHTstimulated
proliferation. Cell cycle analysis showed that this BFA-induced growth
inhibition was associated with a ~75% reduction in the cell number in the S phase and a
concomitant increase in the G1 cell number, indicating a G1 cell cycle arrest. This was
further confirmed by the modulations of specific cell cycle regulators (CDK2, CDK4,
cyclin D1, and p21WAF1), revealed by Western blots. In addition, the growth inhibition
induced by BFA was accompanied by a profound (~90%) loss in AR activity, which
would be presumably attributed to the significantly reduced cellular AR protein level. Conclusions: This study demonstrates that BFA has a potent growth inhibitory activity,
capable of completely inhibiting DHT (androgen)-stimulated LNCaP proliferation. Such
inhibitory action of BFA appears to target cell cycle and AR: BFA led to a G1 cell cycle
arrest and the down-regulation of AR activity/expression, possibly accounting for its
primary growth inhibitory mechanism. Thus, it is conceivable that BFA may provide a
more effective therapeutic modality for patients with hormone-dependent prostate cancer. - 中文關鍵字: --
- 英文關鍵字: --