Abstract
Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an "insulin sensitizer" because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase. This shows that AMP kinase pathway activation by metformin, recently shown to be necessary for metformin inhibition of gluconeogenesis in hepatocytes, is also involved in metformin-induced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment.
Highlights
Metformin (1,1-dimethylbiguanide hydrochloride) is a biguanide commonly used in the treatment of type 2 diabetes mellitus [1]
Metformin acts as a growth inhibitor rather than an insulin sensitizer for MCF-7 human breast cancer cells
Recent work [3] supports the view that the insulin-lowering and glucose-lowering actions of metformin are related to the www.aacrjournals.org suppression of gluconeogenesis, which is a consequence of metformin-stimulated activation of LKB1 and AMP kinase in hepatocytes
Summary
Metformin (1,1-dimethylbiguanide hydrochloride) is a biguanide commonly used in the treatment of type 2 diabetes mellitus [1]. It is frequently referred to as an ‘‘insulin sensitizer’’ because in settings of insulin resistance and hyperinsulinemia, it lowers circulating insulin levels. There is some evidence that suggests that the mechanism of action of metformin involves enhancement of signaling through the insulin receptor, leading to improvement of insulin resistance, followed by reduction in insulin levels [2]. Recent work [3] provides evidence that the key action of metformin is the inhibition of hepatic glucose output by inhibition of gluconeogenesis, with a secondary decline in insulin levels, in the absence of a major effect on insulin signaling. There is strong evidence that in the liver, this mechanism involves the activation of AMP kinase via an LKB1-dependent mechanism [3, 4].
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