title: Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression.
abstract: BACKGROUND
  A long-term treatment with progestin commonly results in progestin resistance in endometrial cancer. So, the aim of this study was to investigate the role of glyoxalase I (GloI), a mediator of chemotherapy resistance, in metformin reversal of progestin resistance in endometrial carcinoma.
  
  
  METHODS
  The proliferation variety of endometrial cancer cells was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-Diphenyltetrazolium (MTT) assay after exposure to medroxyprogesterone acetate, metformin, or both reagents; apoptosis rates were assessed by flow cytometry. Real-time polymerase chain reaction was used to evaluate the effect of small interfering RNA sequence on target gene expression. Western immunoblotting was performed to determine the expression of GloI and the molecules of the mammalian target of rapamycin (mTOR) pathway.
  
  
  RESULTS
  Knocking down GloI sensitized progestin-resistant Ishikawa cells to progestin. Metformin downregulated GloI expression, reversed progestin resistance, enhanced progestin-induced cell proliferation inhibition, and induced apoptosis in progestin-resistant Ishikawa cells. In addition, medroxyprogesterone acetate-induced mTOR phosphorylation was blocked by metformin. Metformin abolishes mTOR phosphorylation and inhibits GloI expression, attenuating proliferation and inducing apoptosis in progestin-resistant Ishikawa cells.
  
  
  CONCLUSIONS
  Dysregulation of GloI expression in endometrial cancer may be part of the molecular mechanisms for progestin resistance.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lingling
authors.initials: L
authors.lastname: Dong
authors.forename: Long
authors.initials: L
authors.lastname: Sui
authors.forename: Yixia
authors.initials: Y
authors.lastname: Yang
authors.forename: Xuelian
authors.initials: X
authors.lastname: Liu
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yu
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Youji
authors.initials: Y
authors.lastname: Feng
mesh_terms: D017209:Apoptosis; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D011372:Progestins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D011372:Progestins; D008687:Metformin; D007791:Lactoylglutathione Lyase