title: Dienogest enhances autophagy induction in endometriotic cells by impairing activation of AKT, ERK1/2, and mTOR.
abstract: OBJECTIVE
  To elucidate the therapeutic mechanisms of progestin and the effects of progesterone and progestin (dienogest) on autophagy induction and regulation in endometriotic cells, specifically the effects of progesterone and dienogest on the phosphoinositide-3/protein kinase B (PI3K-AKT) and mitogen-activated protein kinase kinases 1 and 2 (MEK1/2)/extracellular-signal-regulated kinase 1/2 (ERK1/2) pathways, which activate mammalian target of rapamycin (mTOR), a major negative regulator of autophagy.
  
  
  METHODS
  In vitro study using human endometriotic cyst stromal cells (ECSCs).
  
  
  METHODS
  University medical center.
  
  
  METHODS
  Fifteen patients with ovarian endometrioma.
  
  
  METHODS
  ECSCs treated with progesterone or dienogest.
  
  
  METHODS
  Autophagy as measured by the expression of the microtubule-associated protein light chain 3-II (LC3-II) and autophagosome formation, and levels of AKT, ERK1/2, and mTOR activity to quantify the phosphorylation of AKT, ERK1/2, and S6K (the downstream target of mTOR).
  
  
  RESULTS
  Progesterone treatment had not statistically significant effect on LC3-II expression, autophagosome formation, or phosphorylation of AKT, ERK1/2, or S6K in estrogen-treated ECSCs. However, dienogest treatment up-regulated LC3-II expression and stimulated autophagosome formation. These effects were accompanied by decreased activation of AKT, ERK1/2, and S6K. Furthermore, incubation of ECSCs with AKT and ERK1/2 inhibitors, which mimicked dienogest-mediated inhibition of AKT and ERK1/2 activity, suppressed S6K activity, followed by an increase in LC3-II expression. In addition, cotreatment with dienogest and 3-methyladenine (autophagy inhibitor) decreased the levels of apoptosis of ECSCs compared with the single treatment with dienogest.
  
  
  CONCLUSIONS
  Our results suggest that dienogest treatment of endometriotic cells suppresses AKT and ERK1/2 activity, thereby in turn inhibiting mTOR, inducing autophagy, and promoting apoptosis.
authors.affiliation: Infertility Clinic, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: JongYeob
authors.initials: J
authors.lastname: Choi
authors.affiliation: Center for Clinical Research, Samsung Biomedical Research Institute, Seoul, South Korea.
authors.forename: MinWha
authors.initials: M
authors.lastname: Jo
authors.affiliation: Infertility Clinic, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: EunYoung
authors.initials: E
authors.lastname: Lee
authors.affiliation: Infertility Clinic, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Infertility Clinic, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: dooseok.choi@samsung.com.
authors.forename: DooSeok
authors.initials: D
authors.lastname: Choi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D004715:Endometriosis / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D010048:Ovarian Cysts / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011374:Progesterone / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C023635:dienogest; D011374:Progesterone; D009277:Nandrolone; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: AKT; ERK1/2; autophagy; dienogest; endometriosis