Differential regulation of estrogen receptors α and β by 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol}, a novel resveratrol analog.
Differential regulation of estrogen receptors α and β by 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol}, a novel resveratrol analog.
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4-(E)-{(4-羟基苯基亚氨基)-甲基苯,1,2-二醇}（一种新型白藜芦醇类似物）对雌激素受体 α 和 β 的差异调节。
DOI：
10.1016/j.jsbmb.2014.09.015
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Bhat,HariK
中科院分区：
文献类型：
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作者：
Ronghe,Amruta;Chatterjee,Anwesha;Singh,Bhupendra;Dandawate,Prasad;Murphy,Leigh;Bhat,NimeeK;Padhye,Subhash;Bhat,HariK
乳腺癌是美国女性的第二大死因。雌激素已被认为是乳腺癌发生的主要危险因素。最近的流行病学研究表明，植物雌激素在预防乳腺癌和其他癌症方面具有保护作用。白藜芦醇是一种天然存在的植物雌激素，主要存在于红葡萄、浆果和花生中，已被证明具有强大的抗癌特性。然而，白藜芦醇的不良疗效阻碍了其在临床环境中的使用。为了提高白藜芦醇的疗效，我们合成了一个小的氮杂白藜芦醇类似物组合文库，并测试了它们抑制乳腺癌细胞株生长的能力。我们最近已经证明，其中一个合成的类似物，4-(E)-{(4-hydroxyphenylimino)-methylbenzene，1，2-diol}(HPIMBD)，具有比白藜芦醇更好的抗癌性能。本研究的目的是探讨雌激素受体(ER)α和β的不同调控，作为其抑制乳腺癌的潜在机制。雌激素受体α和β在细胞增殖中的作用是相反的。雌激素受体α介导雌激素的增殖反应，而ERβ具有抗增殖和促凋亡的作用。结果表明，补肾益气汤能显著诱导ERβ的表达，抑制ERα的表达。还抑制癌基因c-myc和细胞周期蛋白Cyclin D1、ERα下游基因和重要的细胞周期调节因子的蛋白表达水平，以及细胞增殖。HPIMBD显著诱导MCF-7细胞抑癌基因p53和p21蛋白表达。此外，在MCF-10A和ERβ-MB-231细胞中，HPIMBD以ERβ依赖的方式抑制c-Myc，提示调控ER是该新化合物的重要上游机制。分子对接研究证实，HPIMBD在ERβ腔中具有更高的亲和力。因此，新的氮杂白藜芦醇类似物HPIMBD可能通过差异性调控ERsα和β的表达来抑制乳腺癌细胞的增殖。
Breast cancer is the second leading cause of death among women in the United States. Estrogens have been implicated as major risk factors in the development of breast neoplasms. Recent epidemiologic studies have suggested a protective role of phytoestrogens in prevention of breast and other cancers. Resveratrol, a naturally occurring phytoestrogen found notably in red grapes, berries and peanuts, has been shown to possess potent anti-cancer properties. However, the poor efficacy of resveratrol has prevented its use in a clinical setting. In order to improve the efficacy of resveratrol, we have synthesized a small combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the growth of breast cancer cell lines. We have recently shown that one of the synthesized analogs, 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol} (HPIMBD), has better anti-cancer properties than resveratrol. The objective of this study was to investigate the differential regulation of estrogen receptors (ERs) α and β as a potential mechanism of inhibition of breast cancer by HPIMBD. Estrogen receptors α and β have been shown to have opposing roles in cellular proliferation. Estrogen receptor α mediates the proliferative responses of estrogens while ERβ plays an anti-proliferative and pro-apoptotic role. We demonstrate that HPIMBD significantly induces the expression of ERβ and inhibits the expression of ERα. HPIMBD also inhibits the protein expression levels of oncogene c-Myc and cell cycle protein cyclin D1, genes downstream to ERα and important regulators of cell cycle, and cellular proliferation. HPIMBD significantly induces protein expression levels of tumor suppressors p53 and p21 in MCF-7 cells. Additionally, HPIMBD inhibits c-Myc in an ERβ-dependent fashion in MCF-10A and ERβ1-transfected MDA-MB-231 cells, suggesting regulation of ERs as an important upstream mechanism of this novel compound. Molecular docking studies confirm higher affinity for binding of HPIMBD in the ERβ cavity. Thus, HPIMBD, a novel azaresveratrol analog may inhibit the proliferation of breast cancer cells by differentially modulating the expressions of ERs α and β.