Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression

J Obstet Gynaecol Res. 2012 Aug;38(8):1077-85. doi: 10.1111/j.1447-0756.2011.01839.x. Epub 2012 Apr 30.

Abstract

Aim: 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.

Material and 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.

Conclusion: Metformin enhances the rate of cell-killing induced by chemotherapeutic agents by repressing GloI expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Endometrioid / drug therapy*
  • Carcinoma, Endometrioid / enzymology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / therapeutic use
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Endometrial Neoplasms / drug therapy*
  • Endometrial Neoplasms / enzymology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Lactoylglutathione Lyase / genetics
  • Lactoylglutathione Lyase / metabolism*
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Paclitaxel / therapeutic use

Substances

  • Antineoplastic Agents
  • Hypoglycemic Agents
  • Metformin
  • Lactoylglutathione Lyase
  • Paclitaxel
  • Cisplatin