Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.
Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.
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DOI：
10.1371/journal.pone.0078479
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bosland MC
中科院分区：
文献类型：
--
作者：
Mahmoud AM;Zhu T;Parray A;Siddique HR;Yang W;Saleem M;Bosland MC
阻断雄激素受体（AR）活性是晚期前列腺癌（PCa）治疗的主要目标。然而，复发与更积极的，激素难治性前列腺癌的出现，其中港口恢复AR活性。这种再激活的一种机制是通过获得AR突变而发生的，所述AR突变使得其能够被各种甾体和非甾体结构激活。因此，有助于AR的不适当（雄激素非依赖性）激活的天然和化学化合物成为深入研究的领域。在这里，我们证明，染料木黄酮，大豆植物雌激素结合的野生型和Thr 877 Ala（T877 A）突变型的AR竞争性与雄激素，然而，它发挥多效性的影响PCa细胞增殖和AR活性取决于AR的突变状态。染料木黄酮以剂量依赖性方式抑制具有野生型AR的LAPC-4细胞的细胞增殖和AR核定位和表达。然而，在表达T877 A突变体AR的LNCaP细胞中，染料木黄酮诱导了一种双相效应，其中生理剂量（0.5-5 μmol/L）刺激细胞生长并增加AR表达和转录活性，较高剂量诱导抑制效应。在用AR突变体T877 A、W741 C和H874 Y转染的PC-3细胞中实现了类似的双相结果。这些研究结果表明，染料木黄酮，在生理浓度下，可能作为一种激动剂和激活突变体AR，可以存在于先进的前列腺癌雄激素消融治疗后。
Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.
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影响因子：
2.8
作者：
Gardner, Christopher D.;Oelrich, Beibei;Liu, Jenny P.;Feldman, David;Franke, Adrian A.;Brooks, James D.
通讯作者：
Brooks, James D.
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Klocker, H
影响因子：
5.6
作者：
Jones, G;Willett, P;Taylor, R
通讯作者：
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