Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction.
Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction.
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黄芩素通过抑制 AR N-C 二聚化和 AR 共激活剂相互作用来抑制雄激素受体 (AR) 介导的前列腺癌进展
DOI：
10.18632/oncotarget.22319
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发表时间：
2017-12-01
期刊：
影响因子：
--
通讯作者：
Wen X
中科院分区：
文献类型：
--
作者：
Xu D;Chen Q;Liu Y;Wen X
雄激素受体（AR）在前列腺癌（PCa）的发生、发展中起着重要作用。使用抗雄激素来减少雄激素生物合成或防止雄激素与AR结合的雄激素剥夺疗法被广泛用于抑制AR介导的PCa生长。然而，大多数ADT可能最终失败，并在12-24个月后出现去势抵抗。我们发现天然产物黄芩素可以通过靶向雄激素诱导的AR反式激活而有效地抑制PCa的进展，而对AR蛋白的表达几乎没有影响。方法采用荧光素酶法检测黄芩素对前列腺癌细胞系LNCaP、CWR 22 Rv 1、C4-2、PC-3和DU 145 AR反式激活的影响。处理48小时后，通过MTT测定法测定细胞生长和IC 50。采用RT-PCR检测AR靶基因PSA、TMPRSS 2和TMEPA 1的mRNA水平。Western blot检测AR和PSA蛋白表达。结果黄芩素天然产物能选择性抑制AR的反式激活，对ERα、GR等其他核受体无明显影响，在低浓度时，2.5 μM黄芩素能有效抑制AR阳性PCa细胞的生长，对AR阴性PCa细胞的生长影响不大。黄芩素抑制AR靶基因PSA、TMPRSS 2和TMEPA 1表达的机制可能与抑制AR N/C二聚化和AR-辅激活因子相互作用有关。结论黄芩素可能通过抑制AR反式激活和AR介导的PCa细胞生长而成为一种有效的抗AR治疗药物。
Background 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 via targeting the androgen-induced AR transactivation with little effect to AR protein expression. Methods 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 IC50 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. Results 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. Conclusions Baicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth.
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影响因子：
3.7
作者：
LeJeune TM;Tsui HY;Parsons LB;Miller GE;Whitted C;Lynch KE;Ramsauer RE;Patel JU;Wyatt JE;Street DS;Adams CB;McPherson B;Tsui HM;Evans JA;Livesay C;Torrenegra RD;Palau VE
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影响因子：
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