Abstract
Multiple lines of evidence suggest that metformin, an antidiabetic drug, exerts anti-tumorigenic effects in different types of cancer. Metformin has been reported to affect cancer cells’ metabolism and proliferation mainly through the activation of AMP-activated protein kinase (AMPK). Here, we show that metformin inhibits, indeed, endometrial cancer cells’ growth and induces apoptosis. More importantly, we report that metformin affects two important pro-survival pathways, such as the Unfolded Protein Response (UPR), following endoplasmic reticulum stress, and the WNT/β-catenin pathway. GRP78, a key protein in the pro-survival arm of the UPR, was indeed downregulated, while GADD153/CHOP, a transcription factor that mediates the pro-apoptotic response of the UPR, was upregulated at both the mRNA and protein level. Furthermore, metformin dramatically inhibited β-catenin mRNA and protein expression. This was paralleled by a reduction in β-catenin transcriptional activity, since metformin inhibited the activity of a TCF/LEF-luciferase promoter. Intriguingly, compound C, a well-known inhibitor of AMPK, was unable to prevent all these effects, suggesting that metformin might inhibit endometrial cancer cells’ growth and survival through the modulation of specific branches of the UPR and the inhibition of the Wnt/β-catenin pathway in an AMPK-independent manner. Our findings may provide new insights on the mechanisms of action of metformin and refine the use of this drug in the treatment of endometrial cancer.
Highlights
Metformin is a biguanide drug that is widely used as the firstline pharmacologic treatment of type 2 diabetes
We report for the first time time that that metformin, metformin, beside beside AMPK, AMPK, is is able able to to affect affect two two molecular molecular pathways pathways that that play play important important roles in endometrial cancer, such as the Unfolded Protein Response (UPR) and the Wnt/β-catenin pathway
CC, which was effective in preventing the phosphorylation of AMPK by metformin (Figure 2A), was ineffective in significantly modifying metformin effects on both endometrial cancer cells’ proliferation and viability (Figure 2B,C)
Summary
Metformin (dimethylbiguanide) is a biguanide drug that is widely used as the firstline pharmacologic treatment of type 2 diabetes. Epidemiological evidence suggests that metformin use lowers cancer risk and reduces the rate of cancer deaths among diabetic patients [3,4,5,6], though lack of effect of metformin in clinical trials has been reported [7] Many of both the systemic indirect and direct effects exerted by metformin on cancer cells are thought to be mediated through the activation of the AMP-activated protein kinase (AMPK), a regulator of energy metabolism usually activated in response to cellular stresses that deplete cellular energy levels, increasing the AMP/ATP ratio [8,9,10,11]. A major UPR effector is the glucose-regulated protein 78
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