Metformin Treatment Exerts Antiinvasive and Antimetastatic Effects in Human Endometrial Carcinoma Cells (original) (raw)

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1Endocrinology and Metabolism Group (B.K.T., R.A., J.C., H.L., L.J.S.C., H.S.R.), Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom;

2Department of Reproductive Medicine and Surgery (B.K.T.), Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, United Kingdom;

*Address all correspondence and requests for reprints to: Bee K. Tan, MBBS, Ph.D., MRCOG, MRCPS (Glasg), Endocrinology and Metabolism Group, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom.

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1Endocrinology and Metabolism Group (B.K.T., R.A., J.C., H.L., L.J.S.C., H.S.R.), Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom;

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1Endocrinology and Metabolism Group (B.K.T., R.A., J.C., H.L., L.J.S.C., H.S.R.), Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom;

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1Endocrinology and Metabolism Group (B.K.T., R.A., J.C., H.L., L.J.S.C., H.S.R.), Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom;

3First Medical Department (H.L.), University of Lübeck Medical School, Lübeck 0451 5000, Germany;

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1Endocrinology and Metabolism Group (B.K.T., R.A., J.C., H.L., L.J.S.C., H.S.R.), Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom;

4Department of Obstetrics & Gynecology (L.J.S.C.), University Hospital, University Hospitals Coventry and Warwickshire National Health Service Trust, Coventry, CV2 2DX, United Kingdom

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1Endocrinology and Metabolism Group (B.K.T., R.A., J.C., H.L., L.J.S.C., H.S.R.), Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom;

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Accepted:

29 November 2010

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Bee K. Tan, Raghu Adya, Jing Chen, Hendrik Lehnert, Louis J. Sant Cassia, Harpal S. Randeva, Metformin Treatment Exerts Antiinvasive and Antimetastatic Effects in Human Endometrial Carcinoma Cells, The Journal of Clinical Endocrinology & Metabolism, Volume 96, Issue 3, 1 March 2011, Pages 808–816, https://doi.org/10.1210/jc.2010-1803
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Context:

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women associated with an increased risk of endometrial hyperplasia. We sought to study the effects of metformin treatment (widely used in the management of PCOS women) on human endometrial adenocarcinoma cells.

Objectives:

To study the effects of metformin treatment on in vitro invasion and metastasis in human endometrial adenocarcinoma cells. Also, given the link between inflammation with endometrial cancer invasion and metastasis, we explored the roles of nuclear factor-κB (NF-κB), matrix metalloproteinases (MMPs) as well as v-akt murine thymoma viral oncogene homolog 1 (Akt) and extracellular signal-regulated kinases (Erk1/2) signaling pathways.

Design:

Sera were obtained from PCOS and control subjects. In vitro invasion were assessed in human endometrial cells (ECC-1 cells) by wound-healing motility and migration assays. NF-κB was studied by stably transfecting ECC-1 cells with a _cis_-reporter plasmid containing luciferase reporter gene linked to five repeats of NF-κB binding sites. The gelatinolytic activities of secreted MMP-2/9 in conditioned media were measured by gelatin zymography. Akt and Erk1/2 phosphorylation were assessed by Western blotting.

Results:

In vitro invasion in ECC-1 cells was significantly attenuated by sera from PCOS women after 6 months of metformin treatment (850 mg twice daily) compared to matched controls (P < 0.01). These effects appear to be associated with NF-κB, MMP-2/9, as well as Akt and Erk1/2 pathways that are known to be important regulators of inflammation, tumor invasion and metastasis.

Conclusions:

Metformin, potentially, may serve as adjuvant treatment in the management of patients with endometrial cancer.

Copyright © 2011 by The Endocrine Society

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