PMID- 21168492
OWN - NLM
STAT- MEDLINE
DCOM- 20110912
LR  - 20211203
IS  - 1879-1220 (Electronic)
IS  - 0960-0760 (Linking)
VI  - 126
IP  - 3-5
DP  - 2011 Sep
TI  - Metformin promotes progesterone receptor expression via inhibition of mammalian 
      target of rapamycin (mTOR) in endometrial cancer cells.
PG  - 113-20
LID - 10.1016/j.jsbmb.2010.12.006 [doi]
AB  - 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-I 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 10muM 
      metformin combined with 1muM 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.
CI  - Copyright (c) 2011. Published by Elsevier Ltd.
FAU - Xie, Ya
AU  - Xie Y
AD  - Department of Obstetrics and Gynecology, Peking University First Hospital, 
      Beijing, China.
FAU - Wang, Yan-Ling
AU  - Wang YL
FAU - Yu, Li
AU  - Yu L
FAU - Hu, Qian
AU  - Hu Q
FAU - Ji, Lei
AU  - Ji L
FAU - Zhang, Yan
AU  - Zhang Y
FAU - Liao, Qin-Ping
AU  - Liao QP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101217
PL  - England
TA  - J Steroid Biochem Mol Biol
JT  - The Journal of steroid biochemistry and molecular biology
JID - 9015483
RN  - 0 (Antineoplastic Agents, Hormonal)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Receptors, Progesterone)
RN  - 9100L32L2N (Metformin)
RN  - C2QI4IOI2G (Medroxyprogesterone Acetate)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Antineoplastic Agents, Hormonal/administration & dosage/pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols
MH  - Carcinoma/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Drug Evaluation, Preclinical
MH  - Endometrial Neoplasms/*genetics/metabolism/pathology
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Hypoglycemic Agents/administration & dosage/pharmacology
MH  - Medroxyprogesterone Acetate
MH  - Metformin/administration & dosage/*pharmacology
MH  - Models, Biological
MH  - Receptors, Progesterone/*genetics/metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
EDAT- 2010/12/21 06:00
MHDA- 2011/09/13 06:00
CRDT- 2010/12/21 06:00
PHST- 2010/10/08 00:00 [received]
PHST- 2010/12/04 00:00 [revised]
PHST- 2010/12/12 00:00 [accepted]
PHST- 2010/12/21 06:00 [entrez]
PHST- 2010/12/21 06:00 [pubmed]
PHST- 2011/09/13 06:00 [medline]
AID - S0960-0760(10)00380-8 [pii]
AID - 10.1016/j.jsbmb.2010.12.006 [doi]
PST - ppublish
SO  - J Steroid Biochem Mol Biol. 2011 Sep;126(3-5):113-20. doi: 
      10.1016/j.jsbmb.2010.12.006. Epub 2010 Dec 17.