Melatonin inhibits both ERα activation and breast cancer cell proliferation induced by a metalloestrogen, cadmium
Melatonin inhibits both ERα activation and breast cancer cell proliferation induced by a metalloestrogen, cadmium
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DOI：
10.1111/j.1600-079x.2006.00315.x
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发表时间：
2006-05-01
影响因子：
10.3
通讯作者：
Sánchez-Barceló, EJ
中科院分区：
文献类型：
--
作者：
Martínez-Campa, C;Alonso-González, C;Sánchez-Barceló, EJ
镉 (Cd) 是一种重金属，通过环境和职业接触影响人类健康。有证据表明镉在多个器官中积累，对人类具有致癌作用。在体内，镉模拟子宫和乳腺中雌激素的作用。在雌激素反应性乳腺癌细胞系中，镉可以刺激增殖，并且还可以独立于雌二醇激活雌激素受体。这种金属雌激素增加 MCF7 细胞中基因表达的能力被抗雌激素阻断，表明这些化合物的活性是由 ER α 介导的。本工作的目的是测试褪黑素是否抑制镉诱导的 MCF7 细胞增殖，并研究褪黑素是否特异性抑制镉诱导的 ER α 反式激活。我们发现褪黑激素可以阻止镉诱导的同步 MCF7 乳腺癌细胞的生长。在瞬时转染实验中，我们证明了 ER α 和 ER β 介导的转录均受到 Cd 的刺激。褪黑素是 Cd 诱导的 ER α 介导的转录的特异性抑制剂，在雌激素反应元件 (ERE) 和含有 AP1 的启动子中，而 ER β 介导的转录不受松果体吲哚抑制。此外，无法结合钙调蛋白的突变体 ER α-（K302G、K303G）可被 Cd 激活，但对褪黑激素治疗变得不敏感。这些结果证明，褪黑激素抑制Cd诱导的MCF7细胞生长，并消除重金属对在ERE-luc和AP1-luc位点表达ERα的细胞的刺激作用。从这些实验中我们可以推断，褪黑激素在 ERE 和 AP1 途径中调节 Cd 诱导的转录。这些结果也强化了褪黑激素的抗雌激素特性作为乳腺癌治疗的宝贵工具的假设。
Cadmium (Cd) is a heavy metal affecting human health both through environmental and occupational exposure. There is evidence that Cd accumulates in several organs and is carcinogenic to humans. In vivo, Cd mimics the effect of estrogens in the uterus and mammary gland. In estrogen-responsive breast cancer cell lines, Cd stimulates proliferation and can also activate the estrogen receptor independent of estradiol. The ability of this metalloestrogen to increase gene expression in MCF7 cells is blocked by anti-estrogens suggesting that the activity of these compounds is mediated by ER alpha. The aims of this work were to test whether melatonin inhibits Cd-induced proliferation in MCF7 cells, and also to study whether melatonin specifically inhibits Cd-induced ER alpha transactivation. We show that melatonin prevents the Cd-induced growth of synchronized MCF7 breast cancer cells. In transient transfection experiments, we prove that both ER alpha- and ER beta-mediated transcription are stimulated by Cd. Melatonin is a specific inhibitor of Cd-induced ER alpha-mediated transcription in both estrogen response elements (ERE)- and AP1-containing promoters, whereas ER beta-mediated transcription is not inhibited by the pineal indole. Moreover, the mutant ER alpha-(K302G, K303G), unable to bind calmodulin, is activated by Cd but becomes insensitive to melatonin treatment. These results proved that melatonin inhibits MCF7 cell growth induced by Cd and abolishes the stimulatory effect of the heavy metal in cells expressing ER alpha at both ERE-luc and AP1-luc sites. We can infer from these experiments that melatonin regulates Cd-induced transcription in both ERE- and AP1 pathways. These results also reinforce the hypothesis of the anti-estrogenic properties of melatonin as a valuable tool in breast cancer therapies.