title: Metformin Suppresses Prostaglandin E2-Induced Cytochrome P450 Aromatase Gene Expression and Activity via Stimulation of AMP-Activated Protein Kinase in Human Endometriotic Stromal Cells.
abstract: BACKGROUND
  Cytochrome P450 aromatase (encoded by the CYP19A1/aromatase gene) plays a critical physiologic role in endometriosis. Metformin is known to suppress prostaglandin E2 (PGE2)-induced CYP19A1 messenger RNA (mRNA) expression in human endometriotic stromal cells (ESCs). However, the possible mechanism behind this suppression remains to be determined.
  
  
  METHODS
  In this study, ESCs were cultured with metformin, PGE2, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitors. Expression of CYP19A1 mRNA and aromatase activity were measured by quantitative polymerase chain reaction and aromatase activity assay, respectively. The binding of the cyclic AMP response element-binding (CREB) protein to CYP19A1 promoter II (PII) was assessed by chromatin immunoprecipitation assay.
  
  
  RESULTS
  We demonstrated that metformin downregulated the expression of aromatase mRNA (32%) and activity (25%) stimulated by PGE2 (4.18-fold and 2.14-fold) in ESCs via stimulation of AMPK. Following PGE2 treatment, there was a marked increase in CREB binding to aromatase PII, while metformin attenuated the above-mentioned stimulation by 67%.
  
  
  CONCLUSIONS
  Metformin could inhibit PGE2-induced CYP19A1 mRNA expression and aromatase activity via AMPK activation and inhibition of CREB to CYP19A1 PII in human ESCs. The results of the present study suggest that metformin may have unique therapeutic potential as an antiendometriotic drug in the future.
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China.
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China.
authors.forename: Ying-Fang
authors.initials: YF
authors.lastname: Zhou
authors.affiliation: Department of Central Laboratory, Peking University First Hospital, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China xueqingqq@hotmail.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xue
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics; D001665:Binding Sites; D016022:Case-Control Studies; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D004715:Endometriosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004717:Endometrium / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D004794:Enzyme Repression; D005260:Female; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D014162:Transfection; D055815:Young Adult
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D008687:Metformin; D001141:Aromatase; C561410:CYP19A1 protein, human; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D015232:Dinoprostone
keywords: AMPK; CREB; CYP19A1; endometriosis; metformin