Anti-tumor activity of metformin: from metabolic and epigenetic perspectives

Abstract

Metformin has been used to treat type 2 diabetes for over 50 years. Epidemiological, preclinical and clinical studies suggest that metformin treatment reduces cancer incidence in diabetes patients. Due to its potential as an anti-cancer agent and its low cost, metformin has gained intense research interest. Its traditional anti-cancer mechanisms involve both indirect and direct insulin-dependent pathways. Here, we discussed the anti-tumor mechanism of metformin from the aspects of cell metabolism and epigenetic modifications. The effects of metformin on anti-cancer immunity and apoptosis were also described. Understanding these mechanisms will shed lights on application of metformin in clinical trials and development of anti-cancer therapy.

Keywords: epigenetic modifications; metabolism; metformin; therapeutic targets.

Figure 1. Effects of metformin in patients with diabetes type 2

Metformin activates LKB1, which then activates AMPK, resulting in differential effects in various tissues. Figures were adapted from [2]. AMPK, AMP-activated protein kinase.

Figure 2. Diagram showing the indirect effect of metformin in suppressing tumorigenesis

Metformin inhibits complex I of the electron transport chain, which leads to increased AMP/ATP ratio and activation of AMPK by LKB1. Activated AMPK inhibits mTOR and its downstream targets by the following two pathways: 1. AMPK stabilizes TSC1/2, which inhibits Rheb, an activator of mTOR; 2. AMPK inhibits mTOR binding protein Raptor. Metformin directly inhibits mTOR by up-regulating REDD1 and suppressing Rags. AMPK, AMP-activated protein kinase; Rheb, Ras homolog enriched in brain; LKB1, liver kinase B1; REDD1, regulated in development and DNA damage response 1; TSC, tuberous sclerosis complex; Rags, Rag GTPases; mTOR, mammalian target of rapamycin; 4EBP1, eukaryotic initiation factor 4E binding protein 1; S6K, S6 kinase.

Figure 3. Schematic representation of the direct effect of metformin in suppressing tumorigenesis

Insulin increases free IGF-1 levels by displacing IGF-1 from its binding protein. IGF-1 stimulates tumorigenesis by Ras/Raf/MEK/ERK and PI3K/PDK1/Akt/mTOR signal pathways. IGF-1 also negatively regulates PTEN, which inhibits PI3K/PDK1/Akt/mTOR signal pathway. Metformin reduces insulin and IGF-1 to inhibit cell proliferation and survival. IGF-1, insulin-like growth factor-1; PI3K, phosphoinositide 3-kinase; PDK1, phosphoinositide-dependent kinase 1; PTEN, phosphatase and tensin homolog.

Figure 4. Schematic representation of metabolism-controlled histone modifications by metformin

Glycolysis determines the NAD⁺/NADH ratio, which enhances the activity of histone deacetylases (sirtuin) to reduce histone acetylation. Glycolysis provides ATP for protein kinase to phosphorylate histones. The TCA cycle intermediate citrate is converted to acetyl-CoA, which is used for HAT-mediated histone acetylation. Another TCA intermediate αKG is used as cofactor to enhance the ability of HDMT to demethylate histones. Glycolysis is required for H2B ubiquitination, but it is unknown if metformin reduces H2B ubiquitination via blocking glycolysis. HAT, histone acetyltransferase; HDMT, histone demethylase; αKG, α-ketoglutarate.