title: Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression.
abstract: OBJECTIVE
  Metformin plays an important role in the inhibition of cancer cell growth and prolongs remission durations. It reverses progestin-resistance in endometrial cancer cells by downregulating glyoxalase I (GloI) expression. This study aimed to investigate the effect of metformin on endometrial cancer cell chemotherapeutic sensitivity and explore the underlying molecular mechanisms.
  
  
  METHODS
  MTT assay was performed to determine the rate of cell death after cisplatin and paclitaxel with or without metformin. Western blot was carried out to analyze GloI expression. SiRNA-targeting of GloI was used to knockdown GloI expression before further treatment with chemotherapeutic agents to examine the effect of GloI downregulation on chemotherapy-induced cell killing. In addition, plasmid transfection was used to overexpress GloI and determine whether high GloI levels blocked metformin-enhanced cell sensitivity to chemotherapy. PCR was used to analyze the efficiency of RNA interference and plasmid transfection.
  
  
  RESULTS
  The addition of metformin enhanced the sensitivity of endometrial cells to cisplatin and paclitaxel, which was associated with reduced levels of GloI expression. Moreover, low-dose chemotherapeutic drugs alone could not significantly reduce GloI expression, whereas the addition of metformin potently downregulated GloI protein levels. Cisplatin and paclitaxel markedly inhibited the proliferative ability of GloI-depleted endometrial cancer cells. However, the overexpression of GloI abolished the effect of metformin-enhanced cell sensitivity to chemotherapeutic drugs.
  
  
  CONCLUSIONS
  Metformin enhances the rate of cell-killing induced by chemotherapeutic agents by repressing GloI expression.
authors.affiliation: Graduate School, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Dong
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Tao
authors.initials: T
authors.lastname: Duan
authors.forename: Youji
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D017239:Paclitaxel / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D008687:Metformin; D007791:Lactoylglutathione Lyase; D017239:Paclitaxel; D002945:Cisplatin