Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells
Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells
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DOI：
10.1016/j.jsbmb.2010.12.006
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发表时间：
2011-09-01
影响因子：
4.1
通讯作者：
Liao, Qin-ping
中科院分区：
文献类型：
--
作者：
Xie, Ya;Wang, Yan-ling;Liao, Qin-ping
Progesterone已被用于子宫内膜癌（EC）的激素治疗多年，但反应率并不令人满意。孕激素受体（PR）的下调是治疗失败的主要原因。胰岛素样生长因子（IGF）系统与EC风险相关，IGF-1可抑制乳腺癌中PR的转录。最近的证据表明，二甲双胍联合口服避孕药可以逆转对孕酮耐药的子宫内膜不典型增生，但其机制尚不清楚。我们试图研究二甲双胍，PR和IGF-II表达的相互作用，并确定二甲双胍是否可以使用石川和HEC-1B EC细胞系增强醋酸甲羟孕酮（MPA）的抗肿瘤作用。我们发现IGF-I和IGF-II均抑制PR A/B mRNA和蛋白表达，而二甲双胍显著促进PR表达。平行地，IGF-II增加AKT和p70 S6 K的磷酸化，而二甲双胍增加AMPK磷酸化并减少p70 S6 K磷酸化。AMPK抑制剂可部分逆转二甲双胍对PRA/B和p70 S6 K的影响。此外，二甲双胍在两种细胞系中协同抗MPA增殖，在10 μ M二甲双胍与1 μ M MPA联合使用时出现峰值协同作用（石川CI=0.20448，HEC-1B CI = 0.12801）。我们的研究结果表明，二甲双胍促进PR的表达，这可以抑制过度表达IGF-II在EC。这种作用部分通过激活AMPK，然后抑制过度激活的mTOR途径介导。(C)2011年由Elsevier Ltd.出版
Progesterone has been used in the hormonal treatment of endometrial cancer (EC) for many years, but the response rates are unsatisfying. The down-regulated progesterone receptor (PR) is the main reason for treatment failure. The insulin-like growth factor (IGF) system is related to EC risk, and IGF-1 can inhibit PR transcription in breast cancer. Recent evidence suggests that metformin-combined oral contraceptives may reverse progesterone-resistant atypical endometrial hyperplasia, but the mechanism is unclear. We attempt to investigate the interaction of metformin, PR and IGF-II expression, and identify whether metformin can enhance the antitumor effect of medroxyprogesterone acetate (MPA) using Ishikawa and HEC-1B EC cell lines. We found that both IGF-I and IGF-II inhibit PR A/B mRNA and protein expression, whereas metformin markedly promotes PR expression. In parallel, IGF-II increases phosphorylation of AKT and p70S6K, while metformin increases AMPK phosphorylation and decreases p70S6K phosphorylation. The effects of metformin on PR A/B and p70S6K are partially reversed by an AMPK inhibitor. Furthermore, metformin synergistically antiproliferates MPA in two cell lines, with the peak synergy occurring with 10 mu M metformin combined with 1 mu M MPA (CI=0.20448 for Ishikawa, CI = 0.12801 for HEC-1B). Our results demonstrate that metformin promotes PR expression, which can be inhibited by overexpressed IGF-II in EC. This effect is partially mediated through activating AMPK followed by inhibiting the overactivated mTOR pathway. (C) 2011 Published by Elsevier Ltd.