Xu Defeng, Chen Qiulu, Liu Yalin, Wen Xingqiao
School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, P.R. China.
Department of Urology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong 518100, P.R. China.
Oncotarget. 2017 Nov 6;8(62):105561-105573. doi: 10.18632/oncotarget.22319. eCollection 2017 Dec 1.
Androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression. Androgen deprivation therapy with antiandrogens to reduce androgen biosynthesis or prevent androgens from binding to AR are widely used to suppress AR-mediated PCa growth. However, most of ADT may eventually fail with development of the castration resistance after 12-24 months. Here we found that a natural product baicalein can effectively suppress the PCa progression targeting the androgen-induced AR transactivation with little effect to AR protein expression.
PCa cells including LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with baicalein and luciferase assay was used to evaluate their effect on the AR transactivation. Cell growth and IC were determined by MTT assay after 48 hrs treatment. RT-PCR was used to evaluate the mRNA levels of AR target genes including PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR and PSA protein expression.
The natural product of baicalein can selectively inhibit AR transactivation with little effect on the other nuclear receptors, including ERα, and GR. At a low concentration, 2.5 μM of baicalein effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Mechanism dissection suggest that baicalein can suppress AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive LNCaP cells and castration resistant CWR22Rv1 cells, that may involve the inhibiting the AR N/C dimerization and AR-coactivators interaction.
Baicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth.
雄激素受体（AR）在前列腺癌（PCa）的发生和发展中起关键作用。使用抗雄激素进行雄激素剥夺疗法以减少雄激素生物合成或阻止雄激素与AR结合，被广泛用于抑制AR介导的PCa生长。然而，大多数雄激素剥夺疗法最终可能会失败，因为在12 - 24个月后会出现去势抵抗。在此，我们发现一种天然产物黄芩素可以通过靶向雄激素诱导的AR反式激活来有效抑制PCa进展，而对AR蛋白表达影响很小。
用黄芩素处理包括LNCaP、CWR22Rv1、C4 - 2、PC - 3和DU145在内的PCa细胞，并使用荧光素酶测定法评估其对AR反式激活的影响。处理48小时后，通过MTT测定法确定细胞生长和IC。RT - PCR用于评估AR靶基因包括前列腺特异抗原（PSA）、跨膜丝氨酸蛋白酶2（TMPRSS2）和前列腺跨膜上皮抗原1（TMEPA1）的mRNA水平。蛋白质印迹法用于测定AR和PSA蛋白表达。
天然产物黄芩素可以选择性抑制AR反式激活，而对包括雌激素受体α（ERα）和糖皮质激素受体（GR）在内的其他核受体影响很小。在低浓度（2.5μM）时，黄芩素有效抑制AR阳性PCa细胞的生长，而对AR阴性PCa细胞影响很小。机制分析表明，黄芩素可以抑制雄激素反应性LNCaP细胞和去势抵抗性CWR22Rv1细胞中AR靶基因（PSA、TMPRSS2和TMEPA1）的表达，这可能涉及抑制AR的N/C二聚化和AR - 共激活因子相互作用。
黄芩素可能因其抑制AR反式激活和AR介导的PCa细胞生长的能力而被开发为一种有效的抗AR疗法。
