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学科主题: 临床医学
题名:
Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells
作者: Xie, Ya1; Wang, Yan-ling2; Yu, Li1; Hu, Qian1; Ji, Lei2; Zhang, Yan1; Liao, Qin-ping1
关键词: Metformin ; Medroxyprogesterone acetate ; Endometrial cancer ; Progesterone receptor ; AMPK ; Mammalian target of rapamycin
刊名: JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
发表日期: 2011-09-01
DOI: 10.1016/j.jsbmb.2010.12.006
卷: 126, 期:3-5, 页:113-120
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Endocrinology & Metabolism
研究领域[WOS]: Biochemistry & Molecular Biology ; Endocrinology & Metabolism
关键词[WOS]: BREAST-CANCER ; IN-VITRO ; GROWTH ; PATHWAY ; CARCINOMA ; ADENOCARCINOMA ; RISK ; AKT
英文摘要:

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.

语种: 英语
所属项目编号: 30801223
项目资助者: National Natural Science Foundation of China
WOS记录号: WOS:000293110300008
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/63630
Appears in Collections:北京大学第一临床医学院_期刊论文

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作者单位: 1.Peking Univ, Hosp 1, Dept Obstet & Gynecol, Beijing 100034, Peoples R China
2.Chinese Acad Sci, State Key Lab Reprod Biol, Inst Zool, Beijing 100080, Peoples R China

Recommended Citation:
Xie, Ya,Wang, Yan-ling,Yu, Li,et al. Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells[J]. JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY,2011,126(3-5):113-120.
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