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Metformin Reverses Progestin Resistance in Endometrial Cancer Cells by Downregulating GloI Expression
  1. Zhenbo Zhang, MD*,
  2. Lingling Dong, MSc,,
  3. Long Sui, MD§,
  4. Yixia Yang, MSc*,
  5. Xuelian Liu, MSc*,
  6. Yinhua Yu, MD§,
  7. Yaping Zhu, MD* and
  8. Youji Feng, MD*
  1. * Department of Obstetrics and Gynecology, First People's Hospital, Shanghai Jiao Tong University;
  2. Graduate School, Shanghai Medical College Fudan University;
  3. Shanghai First Maternal and Fetal Care Hospital, Tongji University; and
  4. § Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
  1. Address correspondence and reprint requests to Yaping Zhu, MD, or Youji Feng, MD, Department of Obstetrics & Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, 100 Haining Rd, Shanghai, China 200080. E-mail: zhuyp63{at} or fengyj4806{at}


Introduction: 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.

Result: 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.

  • GloI
  • Apoptosis
  • Progestin resistance
  • Endometrial cancer
  • Metformin

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  • The authors have no financial interest in this study.