Abstract
The incidence of endometrial cancer (EC) has increased over the past years and mainly affects women above the age of 45 years. Metabolic diseases such as obesity and type II diabetes mellitus as well as associated conditions like polycystic ovary syndrome (PCOS), insulin resistance and hyperinsulinemia lead to elevated levels of circulating estrogens. Increased estrogen concentrations, in turn, further trigger the proliferation of endometrial cells and thus promote EC development and progression, especially in the absence of progesterone as seen in postmenopausal women. Elevated blood glucose levels in diabetic patients further contribute to the risk of EC development. Metformin is an insulin-sensitizing biguanide drug, commonly used in the treatment of type II diabetes mellitus, especially in obese patients. Besides its effects on glucose metabolism, metformin displayed anti-cancer effects in various cancer types, including EC. Direct anti-cancer effects of metformin target signaling pathways that are involved in cellular growth and proliferation, e.g. the AKT/PKB/mTOR pathway. Further proteins and pathways have been suggested as potential targets, but the underlying mechanism of action of metformin’s anti-cancer activity is still not completely understood. In the present study, the effects of metformin on protein expression were investigated in the human EC cell line HEC-1A using an affinity proteomic approach. Cells were treated with 0.5 mmol/L metformin over a period of 7 days and changes in the expression pattern of 1,300 different proteins were compared to the expression in untreated control cells as well as insulin-treated cells. Insulin treatment (100 ng/mL) was incorporated into the study in order to implement a model for insulin resistance and associated hyperinsulinemia, conditions that are often observed in obese and diabetic patients. Furthermore, the culture medium was supplemented with 10 nmol/L ß-estradiol (E2) during treatments to mimic increased estrogen levels, a common risk factor for EC development. Based on the most prominent and significant changes in expression, a set of 80 proteins was selected and subjected to a more detailed analysis. The data revealed that metformin and insulin targeted similar pathways in the present study and mostly acted on proteins related to proliferation, migration and tumor immune response. These pathways may be affected in a tumor-promoting as well as a tumor-suppressing way by either metformin treatment or insulin supplementation. The consequences for the cells resulting from the detected expression changes were discussed in detail for several proteins. The presented data helps identify potential targets affected by metformin treatment in EC and allows for a better understanding of the mechanism of action of the biguanide drug’s anti-cancer activity. However, further investigations are necessary to confirm the observations and conclusions drawn from the presented data after metformin administration, especially for proteins that were regulated in a favorable way, i.e. AKT3, CCND2, CD63, CD81, GFAP, IL5, IL17A, IRF4, PI3, and VTCN1. Further proteins might be of interest, where metformin counteracted unfavorable effects that have been induced by hyperinsulinemia.
Highlights
Endometrial cancer (EC) is the 6th most common cancer in women and constitutes the leading malignancy of the female reproductive system in developed countries [1]
Further investigations are necessary to confirm the observations and conclusions drawn from the presented data after metformin administration, especially for proteins that were regulated in a favorable way, i.e. AKT3, cyclin D2 (CCND2), cluster of differentiation 63 (CD63), CD81, glial fibrillary acidic protein (GFAP), IL5, IL17A, interferon regulatory factor 4 (IRF4), PI3, and VTCN1
Differential changes in the expression of 12 out of 47 proteins overlapped with insulin-induced changes compared to control samples (Table 2) and 17 proteins were differentially expressed after metformin administration when compared to an hyperinsulinemic environment (CCND2, CD2, CD63, CD81, CDCP1, CTGF, F3, FGF2, GFAP, GUSB, HAVCR1, IRF4, PI3, PLAUR, PPIA, UBE2T, VTCN1)
Summary
Endometrial cancer (EC) is the 6th most common cancer in women and constitutes the leading malignancy of the female reproductive system in developed countries [1]. The high incidence and mortality in developed countries could be related to a higher prevalence of common risk factors such as obesity and type II diabetes mellitus [1, 7, 8]. Obesity and obesity-associated diseases such as polycystic ovary syndrome (PCOS) lead to elevated levels of circulating estrogens that, in turn, increase proliferation of endometrial cells and promote EC development, especially in the absence of progesterone [9,10,11]. Elevated blood glucose levels of diabetic patients may further contribute to the risk of EC development via an increased glycolytic-lipogenic metabolism and the insulin-like growth factor (IGF) signaling pathway [12, 13]
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