Molis T M, Spriggs L L, Hill S M
Department of Anatomy, Tulane University School of Medicine, New Orleans, Louisiana 70112.
Mol Endocrinol. 1994 Dec;8(12):1681-90. doi: 10.1210/mend.8.12.7708056.
Melatonin, the hormonal product of the pineal gland, has been shown to inhibit the development of mammary tumors in vivo and the proliferation of MCF-7 human breast cancer cells in vitro by mechanisms not yet identified. However, previous studies have demonstrated that melatonin significantly decreased estrogen-binding activity and the expression of immunoreactive estrogen receptor (ER) in MCF-7 breast cancer cells. To determine the mechanism(s) by which melatonin regulates ER expression in MCF-7 cells, the relationship between the level of steady state ER mRNA and the rate of ER gene transcription were examined in response to melatonin. Physiological concentrations of melatonin decreased steady state levels of ER mRNA expression in a dose- and time-specific manner. This decrease was not dependent upon the presence of estrogen since similar decreases in steady state ER mRNA levels were seen in MCF-7 cells cultured in both complete and estrogen-depleted media. The decreased expression of ER mRNA in response to melatonin appears to be directly related to the suppression of transcription of the ER gene. This regulation is independent of the synthesis of new proteins, as cycloheximide was unable to block the melatonin-induced decrease of steady-state ER mRNA levels. The down-regulation of ER by melatonin appears to not be mediated via a direct interaction with the ER and subsequent feedback on its own expression, since melatonin treatment did not alter the transcriptional regulatory ability of the fully activated wild type ER or a constitutively active hormone-binding domain-deleted ER variant. In addition, the stability of the ER transcript was unaffected by melatonin. Thus, it appears that the antiproliferative actions of this pineal indoleamine are mediated, at least in part, through the suppression of the transcription of the ER gene in MCF-7 human breast cancer cells.
褪黑素是松果体分泌的一种激素产物，已被证明在体内可抑制乳腺肿瘤的发展，在体外可抑制MCF-7人乳腺癌细胞的增殖，但其作用机制尚未明确。然而，先前的研究表明，褪黑素可显著降低MCF-7乳腺癌细胞中的雌激素结合活性和免疫反应性雌激素受体（ER）的表达。为了确定褪黑素调节MCF-7细胞中ER表达的机制，研究了在褪黑素作用下，ER mRNA稳态水平与ER基因转录速率之间的关系。生理浓度的褪黑素以剂量和时间特异性的方式降低了ER mRNA表达的稳态水平。这种降低并不依赖于雌激素的存在，因为在完全培养基和雌激素缺乏培养基中培养的MCF-7细胞中，ER mRNA稳态水平都出现了类似的降低。褪黑素引起的ER mRNA表达降低似乎与ER基因转录的抑制直接相关。这种调节与新蛋白质的合成无关，因为环己酰亚胺无法阻断褪黑素诱导的ER mRNA稳态水平的降低。褪黑素对ER的下调似乎不是通过与ER的直接相互作用及其自身表达的反馈介导的，因为褪黑素处理并未改变完全激活的野生型ER或组成型活性激素结合结构域缺失的ER变体的转录调节能力。此外，ER转录本的稳定性不受褪黑素的影响。因此，这种松果体吲哚胺的抗增殖作用似乎至少部分是通过抑制MCF-7人乳腺癌细胞中ER基因的转录来介导的。
