Melatonin, an endogenous-specific inhibitor of estrogen receptor α via calmodulin
Melatonin, an endogenous-specific inhibitor of estrogen receptor α via calmodulin
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DOI：
10.1074/jbc.m403140200
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发表时间：
2004-09-10
影响因子：
4.8
通讯作者：
Ramos, S
中科院分区：
文献类型：
--
作者：
del Río, B;Pedrero, JMG;Ramos, S
褪黑激素是一种吲哚激素，主要由松果体产生。我们之前已经证明，褪黑激素通过损害雌激素受体 (ER) 途径来干扰 MCF7 细胞中的雌激素 (E-2) 信号传导。在这里，我们描述了其作用机制的特征，表明褪黑激素是 E-2 诱导的 ERα 介导的转录的特异性抑制剂，在雌激素反应元件和 AP1 的启动子中，而 ERbeta 介导的反式激活在某些启动子上不受抑制甚至激活。我们发现MCF-7细胞对褪黑激素的敏感性取决于ERα/ERβ比率，ERβ的异位表达导致MCF-7细胞对该激素变得不敏感。褪黑激素作为钙调蛋白拮抗剂，诱导 ERα-钙调蛋白 (CaM) 复合物构象变化，从而损害 E-2.ERα.CaM 复合物与 DNA 的结合，从而阻止 ERα 依赖性转录。此外，突变体 ERα（K302G、K303G）无法结合钙调蛋白，对褪黑激素变得不敏感。褪黑激素的作用是特定的，因为其他相关吲哚既不与 CaM 相互作用，也不抑制 ERα 介导的反式激活。有趣的是，褪黑激素不会影响共激活剂与 ERα 的结合，这表明褪黑激素的作用不同于目前用于乳腺癌治疗的抗雌激素。因此，它们在不同水平上靶向 ERα，代表了控制 ERα 活性的两种独立方式。因此，可以想象，这是褪黑激素和现有抗雌激素药物的协同药理作用。
Melatonin is an indole hormone produced mainly by the pineal gland. We have previously demonstrated that melatonin interferes with estrogen (E-2) signaling in MCF7 cells by impairing estrogen receptor (ER) pathways. Here we present the characterization of its mechanism of action showing that melatonin is a specific inhibitor of E-2-induced ERalpha-mediated transcription in both estrogen response element- and AP1-containing promoters, whereas ERbeta-mediated transactivation is not inhibited or even activated at certain promoters. We show that the sensitivity of MCF-7 cells to melatonin depends on the ERalpha/ERbeta ratio, and ectopic expression of ERbeta results in MCF-7 cells becoming insensitive to this hormone. Melatonin acts as a calmodulin antagonist inducing conformational changes in the ERalpha-calmodulin (CaM) complex, thus impairing the binding of E-2.ERalpha.CaM complex to DNA and, therefore, preventing ERalpha-dependent transcription. Moreover the mutant ERalpha (K302G, K303G), unable to bind calmodulin, becomes insensitive to melatonin. The effect of melatonin is specific since other related indoles neither interact with CaM nor inhibit ERalpha-mediated transactivation. Interestingly, melatonin does not affect the binding of coactivators to ERalpha, indicating that melatonin action is different from that of current therapeutic anti-estrogens used in breast cancer therapy. Thus, they target ERalpha at different levels, representing two independent ways to control ERalpha activity. It is, therefore, conceivably a synergistic pharmacological effect of melatonin and current anti-estrogen drugs.