title: Dienogest, a synthetic progestin, inhibits the proliferation of immortalized human endometrial epithelial cells with suppression of cyclin D1 gene expression.
abstract: Dienogest is a specific progesterone receptor agonist with potent oral endometrial activity and is used in the treatment of endometriosis. In this study, we examined the direct effects of dienogest on the proliferation of human endometrial epithelial cells using an immortalized cell line. 5-Bromo-2'-deoxyuridine incorporation into the cells was inhibited by dienogest and by progesterone (P(4)) in dose-dependent fashion at concentrations of 10(-8) mol/l or higher. To identify the target genes of dienogest and P(4), we screened the expression of 84 genes related to cell cycle regulation by real-time polymerase chain reaction after 6 h of treatment at a concentration of 10(-7) mol/l. Results showed that only cyclin D1 expression was significantly down-regulated, although expression of the other genes did not significantly change after dienogest or P(4) treatment compared with the control. In a time-course study during the first 24 h after drug treatment, dienogest and P(4) each produced a lasting decrease in the expression of cyclin D1 mRNA, followed by a decrease in cyclin E1 mRNA but not an increase in the expression of cell cycle inhibitor genes (p21, p27 and p53). These findings suggest that dienogest directly inhibits the proliferation of human endometrial epithelial cells with suppression of cyclin D1 gene expression.
authors.affiliation: Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., Gotemba 412-8524, Japan. shimizuy@mochida.co.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Takashi
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Shizuka
authors.initials: S
authors.lastname: Mita
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mizuguchi
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.forename: Masaki
authors.initials: M
authors.lastname: Inoue
authors.forename: Satoru
authors.initials: S
authors.lastname: Kyo
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; D006727:Hormone Antagonists; D015513:Oncogene Proteins; D019938:Cyclin D1; C023635:dienogest; D009277:Nandrolone