Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors.
Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors.
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褪黑激素和生长因子对 MCF-7 乳腺癌细胞中雌激素受体的反式激活。
DOI：
10.1016/s0303-7207(98)00095-1
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发表时间：
1998
影响因子：
4.1
通讯作者：
Hill,SM
中科院分区：
文献类型：
--
作者：
Ram,PT;Kiefer,T;Silverman,M;Song,Y;Brown,GM;Hill,SM
松果体激素褪黑激素可抑制雌激素受体 (ER) 阳性 MCF-7 人乳腺癌细胞的增殖，调节 ER mRNA 和蛋白质表达，并且似乎具有血清依赖性，表明褪黑激素和血清成分之间存在相互作用。为了检查褪黑激素对 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 细胞来进行 ER 反式激活测定。 MCF-7 细胞用褪黑激素预处理短短 5 分钟，然后用表皮生长因子 (EGF) 或胰岛素处理，导致 ER 发生不依赖于雌激素的反式激活。当单独使用时，这些化合物均不会反式激活 ER。添加抗雌激素 ICI 164 384 后，褪黑激素和 EGF 反式激活 ER 的能力被消除，这表明褪黑激素和 EGF 共同反式激活 ER。 ER 反式激活的调节与丝裂原激活蛋白激酶活性和 ER 磷酸化的变化相关。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，表明 G 蛋白偶联褪黑激素受体途径和 EGF/胰岛素酪氨酸激酶受体途径在调节 ER 反式激活中存在交互作用。褪黑激素与 EGF 结合反式激活 ER 的能力与褪黑激素观察到的生长抑制作用之间的确切关系尚不清楚。尽管褪黑素和EGF反式激活ER，但这种反式激活可能不会导致雌激素反应基因的完全转录，而是使ER难以被雌二醇激活，从而阻断雌二醇的有丝分裂作用。
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 164 384, 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 Gαi-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.