Ram P T, Kiefer T, Silverman M, Song Y, Brown G M, Hill S M
Department of Anatomy, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Mol Cell Endocrinol. 1998 Jun 25;141(1-2):53-64. doi: 10.1016/s0303-7207(98)00095-1.
The pineal hormone, melatonin, inhibits proliferation of estrogen receptor (ER)-positive MCF-7 human breast cancer cells, modulates both ER mRNA and protein expression, and appears to be serum dependent, indicating interaction between melatonin and serum components. To examine the effects of melatonin on ER activity, ER transactivation assays were performed by transiently transfecting MCF-7 cells with an ERE-luciferase reporter construct. MCF-7 cells pre-treated with melatonin for as little as 5 min followed by either epidermal growth factor (EGF) or insulin resulted in the estrogen-independent transactivation of the ER. None of the compounds when used alone transactivated the ER. The ability of melatonin and EGF to transactivate the ER was abolished by the addition of the antiestrogen, ICI 164384, suggesting that melatonin and EGF co-operate to transactivate the ER. The modulation of ER transactivation was associated with changes in mitogen activated protein kinase activity and ER phosphorylation. This ER transactivation was blocked by pertussis toxin, a Galpha i-protein-coupled receptor inhibitor, suggesting cross talk between the G-protein-coupled melatonin receptor pathway and the EGF/insulin tyrosine kinase receptor pathways in modulating ER transactivation. Exactly how the ability of melatonin in combination with EGF to transactivate the ER relates to melatonin's observed growth suppressive effects is not clear. It is possible that, although melatonin and EGF transactivate the ER, this transactivation does not result in the full transcription of estrogen-responsive genes, but rather, makes the ER refractory to activation by estradiol, thus, blocking the mitogenic actions of estradiol.
松果体激素褪黑素可抑制雌激素受体（ER）阳性的MCF-7人乳腺癌细胞的增殖，调节ER mRNA和蛋白表达，且似乎依赖血清，这表明褪黑素与血清成分之间存在相互作用。为了研究褪黑素对ER活性的影响，通过用ERE-荧光素酶报告基因构建体瞬时转染MCF-7细胞进行ER反式激活测定。用褪黑素预处理MCF-7细胞仅5分钟，随后加入表皮生长因子（EGF）或胰岛素，可导致ER的雌激素非依赖性反式激活。单独使用这些化合物时均不能反式激活ER。加入抗雌激素药物ICI 164384可消除褪黑素和EGF反式激活ER的能力，这表明褪黑素和EGF协同反式激活ER。ER反式激活的调节与丝裂原活化蛋白激酶活性和ER磷酸化的变化有关。这种ER反式激活被百日咳毒素（一种Gαi蛋白偶联受体抑制剂）阻断，这表明在调节ER反式激活过程中，G蛋白偶联的褪黑素受体途径与EGF/胰岛素酪氨酸激酶受体途径之间存在相互作用。目前尚不清楚褪黑素与EGF联合反式激活ER的能力与褪黑素所观察到的生长抑制作用之间的确切关系。有可能的是，尽管褪黑素和EGF反式激活了ER，但这种反式激活不会导致雌激素反应基因的完全转录，而是使ER对雌二醇的激活产生不应性，从而阻断雌二醇的促有丝分裂作用。
