The role of AMPK/mTOR signaling pathway in anticancer activity of metformin

Abstract

Metformin (MTF) is a widely used drug for the treatment of diabetes mellitus type 2 (DM2) and frequently used as an adjuvant therapy for polycystic ovarian syndrome, metabolic syndrome, and in some cases also tuberculosis. Its protective effect on the cardiovascular system has also been described. Recently, MTF was subjected to various analyzes and studies that showed its beneficial effects in cancer treatment such as reducing cancer cell proliferation, reducing tumor growth, inducing apoptosis, reducing cancer risk in diabetic patients, or reducing likelihood of relapse. One of the MTF's mechanisms of action is the activation of adenosine-monophosphate-activated protein kinase (AMPK). Several studies have shown that AMPK/mammalian target of rapamycin (mTOR) pathway has anticancer effect in vivo and in vitro. The aim of this review is to present the anticancer activity of MTF highlighting the importance of the AMPK/mTOR pathway in the cancer process.

Fig. 1

The various diseases where MTF has a beneficial effect.

Fig. 2

The role of MTF in metabolism and cancer process through AMPK/mTOR signaling pathway. AMPK activation inhibits mTORC1, leading to decreasing of cell growth, angiogenesis and Warburg effect, and increasing of apoptosis. ATP adenosine-triphosphate, AMP adenosine-monophosphate, ATM ataxia telangiectasia mutated, LKB1 liver kinase B1, AMPK adenosine-monophosphate-activated protein kinase, HMG-CoA β-Hydroxy β-methylglutaryl-coenzyme-A, IGF-1 insulin-like growth factor 1, IGF-R insulin-like growth factor receptor, PI3K phosphatidylinositol-3-kinase, Akt protein kinase B, mTORC1 mammalian target of rapamycin complex 1, TSC1,2 tuberous sclerosis complex 1,2, Rheb Ras homolog enriched in brain, RAPTOR regulatory-associated protein of mTOR, mTOR mammalian target of rapamycin, p53 tumor suppressor protein, p70S6K p70S6 kinase, HIF-1α hypoxia-inducible factor 1α, VEGF vascular endothelial growth factor, BAX BCL-2 associated X protein.