Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase
Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase
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DOI：
10.1007/s10549-010-0834-y
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发表时间：
2010-09-01
影响因子：
3.8
通讯作者：
Simpson, Evan R.
中科院分区：
文献类型：
--
作者：
Brown, Kristy A.;Hunger, Nicole I.;Simpson, Evan R.
AMP激活的蛋白激酶(AMPK)被认为是能量稳态的主要调节者。与AMPK-Kinase LKB1一起，它已被证明通过抑制乳房内芳香化酶的表达，从而抑制雌激素的产生，在肥胖和绝经后乳腺癌之间提供了分子联系。抗糖尿病药物二甲双胍可以增加AMPK的活性，因此被认为可以抑制原代人类乳房脂肪基质细胞中芳香化酶的表达。结果表明，在浓度为10和50 mU时，二甲双胍可显著降低佛波酯/佛波酯(FSK/PMA)诱导的芳香化酶的表达，50 mU/mM的二甲双胍可显著增强Thr172处AMPK的磷酸化水平，这与二甲双胍增强AMPK活性的假说一致。有趣的是，二甲双胍还导致LKB1蛋白表达和启动子活性显著增加，从而首次提供了一种额外的机制，通过它激活AMPK。此外，二甲双胍抑制CRTC2的核转位，CRTC2是一种CREB辅助激活剂，可增加芳香酶的表达，而芳香酶也是AMPK的直接下游靶点。总体而言，这些结果表明，二甲双胍将减少乳房内雌激素的局部产生，从而提供一种新的关键治疗工具，可以用于新的佐剂和佐剂环境，也可以作为肥胖女性的预防措施。
AMP-activated protein kinase (AMPK) is recognized as a master regulator of energy homeostasis. In concert with the AMPK-kinase LKB1, it has been shown to provide a molecular link between obesity and postmenopausal breast cancer via its actions to inhibit aromatase expression, hence estrogen production, within the breast. The anti-diabetic drug metformin is known to increase the activity of AMPK and was therefore hypothesized to inhibit aromatase expression in primary human breast adipose stromal cells. Results demonstrate that metformin significantly decreases the forskolin/phorbol ester (FSK/PMA)-induced expression of aromatase at concentrations of 10 and 50 mu M. Consistent with the hypothesized actions of metformin to increase AMPK activity, treatment with 50 mu M metformin results in a significant increase in phosphorylation of AMPK at Thr172. Interestingly, metformin also causes a significant increase in LKB1 protein expression and promoter activity, thereby providing for the first time an additional mechanism by which metformin activates AMPK. Furthermore, metformin inhibits the nuclear translocation of CRTC2, a CREB-coactivator known to increase aromatase expression which is also a direct downstream target of AMPK. Overall, these results suggest that metformin would reduce the local production of estrogens within the breast thereby providing a new key therapeutic tool that could be used in the neoadjuvant and adjuvant settings and conceivably also as a preventative measure in obese women.