4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}, 1 a novel resveratrol analog, differentially regulates estrogen receptors α and β in breast cancer cells.
4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}, 1 a novel resveratrol analog, differentially regulates estrogen receptors α and β in breast cancer cells.
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DOI：
10.1016/j.taap.2016.03.003
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发表时间：
2016-06-15
影响因子：
3.8
通讯作者：
Bhat HK
中科院分区：
文献类型：
--
作者：
Ronghe A;Chatterjee A;Singh B;Dandawate P;Abdalla F;Bhat NK;Padhye S;Bhat HK
乳腺癌是全世界的公共卫生问题。长期接触雌激素与乳腺肿瘤的发生有关。流行病学和实验证据表明植物雌激素对乳腺癌具有化学预防作用。白藜芦醇是一种天然存在的植物雌激素，已被证明具有有效的抗癌特性。然而，较差的疗效和生物利用度阻碍了白藜芦醇在临床的使用。为了解决这些问题，我们合成了阿扎藜芦醇类似物的组合文库，并测试了它们抑制乳腺癌细胞增殖的能力。我们最近表明，4-(E)-{(p-tolylimino)-methylphene-1,2-diol} (TIMBD) 比白藜芦醇和我们迄今为止合成的任何其他白藜芦醇类似物具有更好的抗癌特性。本研究的目的是研究 TIMBD 对乳腺癌细胞系中雌激素受体 (ER) α 和 β 的调节作用。我们证明 TIMBD 显着诱导 ERβ 的 mRNA 和蛋白表达水平并抑制 ERα 的 mRNA 和蛋白表达水平。 TIMBD 抑制癌基因 c-Myc 和细胞周期蛋白 cyclin D1 的 mRNA 和蛋白表达水平，它们是细胞增殖的重要调节因子。 TIMBD 显着诱导 MCF-7 细胞中抑癌基因 p53 和 p21 的蛋白表达水平。 TIMBD 在 MCF-10A 和 ERβ1 转染的 MDA-MB-231 细胞中以 ERβ 依赖性方式抑制 c-Myc，表明 ER 的调节是该类似物的重要上游机制。 ERβ在TIMBD抑制增殖过程中起部分作用，而ERα过表达并不显着影响TIMBD的抑制作用。
Breast cancer is a public health concern worldwide. Prolonged exposure to estrogens has been implicated in the development of breast neoplasms. Epidemiologic and experimental evidence suggest a chemopreventive role of phytoestrogens in breast cancers. Resveratrol, a naturally occurring phytoestrogen, has been shown to have potent anti-cancer properties. However, poor efficacy and bioavailability have prevented the use of resveratrol in clinics. In order to address these problems, we have synthesized a combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the proliferation of breast cancer cells. We have recently shown that 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD), has better anti-cancer properties than resveratrol and any other resveratrol analog we have synthesized so far. The objective of this study was to investigate the regulation of estrogen receptors (ERs) α and β by TIMBD in breast cancer cell lines. We demonstrate that TIMBD significantly induces the mRNA and protein expression levels of ERβ and inhibits that of ERα. TIMBD inhibits mRNA and protein expression levels of oncogene c-Myc, and cell cycle protein cyclin D1, which are important regulators of cellular proliferation. TIMBD significantly induces protein expression levels of tumor suppressor genes p53 and p21 in MCF-7 cells. TIMBD 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 analog. ERβ plays a partial role in inhibition of proliferation by TIMBD while ERα overexpression does not significantly affect TIMBD’s inhibition.