Int J Cancer 2012 Jan;130 (1): 200-12. [IF:4.926]
Galbanic acid decreases androgen receptor abundance and signaling and induces G(1) arrest in prostate cancer cells.
Zhang Y , Kim KH , Zhang W , Guo Y , Kim SH , Lü J .
The Hormel Institute, University of Minnesota, Austin, MN; Institute of Urology and National Urological Cancer Center, Peking University First Hospital, Peking University, Beijing, China.
北京大学第一医院，美国明尼苏达大学荷美尔研究所，泌尿外科研究所和全国泌尿科癌症研究中心
Abstract
Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(-) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(-) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA downregulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide (Bic), LNCaP cell culture assays did not detect agonist activity of GBA. GBA and Bic exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G(1) arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D(1) without the causal involvement of cyclin-dependent kinase (CDK) inhibitory proteins P21(Cip1) and P27(Kip1) . In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and Bic with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multitargeting drug candidate for the prevention and therapy of PCa.
摘要
雄性激素受体信号对前列腺癌的产生和进展是关键的。我们比较AR(+) LNCaP 和 LNCaP C4-2 对 AR(-) DU145 和PC-3 PCa细胞系对草药中提纯的GBA的生长反应，并且评价他们对AR信号和细胞周期调节通路的联系。我们的结果显示，比起AR(-) PCa来，GBA更喜欢抑制AR(+) PCa细胞生长。GBA诱发caspase介导的细胞凋亡，后者被caspase抑制剂减弱。通过促进proteasomal的降解，亚凋亡的GBA下调LNCaP 细胞的AR蛋白，并且抑制AR-依赖的转录，不影响AR核迁移。而对接模拟预测GBA和AR配体粘合域的连接与AR拮抗药bicalutamide (Bic)有相似性和类似性。LNCaP培养化验没发现GBA的激动活性。GBA和Bic合用时对细胞生长产生更大的抑制效应。 亚凋亡GBA诱发和cyclin/CDK4/6通路抑制相关的G(1)期停止。尤其细胞周期蛋白D(1)通路没细胞周期蛋白依赖的激酶抑制蛋白P21(Cip1) 和P27(Kip1)的参与。总的来说，就AR蛋白转变和小的兴奋作用而言，抗AR化合物的GBA的新奇之处在于GBA和Bic之间的不同。我们观察到的抗AR和细胞周期停止作用和被报告的抗血管再生作用暗示了GBA为一PCa预防和治疗的多靶点药。
