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.