Abstract
Although a number of in vitro studies have demonstrated the antiproliferative, anti-invasive, and antimetastatic effects of metformin in multiple cancer cell types, its cellular and molecular mechanisms of anti-cancer action in the endometrium of women with polycystic ovary syndrome (PCOS) have not yet been fully elucidated. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) are known to be involved in metformin uptake and excretion in cells. In this article, we discuss the novel therapeutic possibilities for early-stage endometrial carcinoma (EC) in women with PCOS focusing on metformin, which might have a direct effect in the endometrium through the OCTs and MATEs. We then review the molecular mechanism(s) of the action of metformin in the endometrium and highlight possible mechanistic insights into the inhibition of cell proliferation and tumor growth and, ultimately, the reversal of early-stage EC into normal endometria in women with PCOS.
Highlights
The clinical problem Endometrial carcinoma (EC) is the second most frequent gynecological malignancy in women with 49,560 cases reported and 8,190 deaths from this disease in the US in 2013 [1]
A recent study from our laboratory has shown that a combination of metformin and oral contraceptives is capable of reverting early-stage EC into normal endometria in addition to improving insulin resistance in women with polycystic ovary syndrome (PCOS) [49]
Because adenosine monophosphateactivated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and glucose transport protein 4 (GLUT4) are considered to be central factors that are targeted by metformin, and because various Organic cation transporter (OCT) and Multidrug and toxin extrusion protein (MATE) that mediate the metformin uptake and excretion are present in endometrial epithelial and stromal cells, we propose the following two mechanisms of metformin-induced inhibition of the phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (AKT)/mTOR cascade in PCOS women with early stage EC. (1) Metformin activates the AMPK pathway in the liver and suppresses hepatic gluconeogenesis
Summary
The clinical problem Endometrial carcinoma (EC) is the second most frequent gynecological malignancy in women with 49,560 cases reported and 8,190 deaths from this disease in the US in 2013 [1]. A recent study from our laboratory has shown that a combination of metformin and oral contraceptives is capable of reverting early-stage EC into normal endometria in addition to improving insulin resistance in women with PCOS [49] This is a promising result, we note that our preliminary report must be taken with caution and that further research is certainly needed before co-treatment with metformin and oral contraceptives can be recommended in clinical practice. Glucose uptake depends on the level of GLUT4 expression [99], and treatment with metformin increases GLUT4 mRNA and protein expression in endometrial cells from women with PCOS in vivo [81,103] and in vitro [104], possibly through the activation of AMPK and its downstream targets such as myocyte enhancer factor 2A [81].
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