Fig. 3

Metformin and oncosignaling pathways. The main anti-proliferative effect of metformin depends on inhibition of mTORC1. Inhibition of mitochondrial complex I by metformin and decreased ATP/AMP ratio activates the LKB1/AMPK pathway. AMPK is one of the main inhibitors of mTOR by activating TSC1/2 and downregulates mTORC1. However, the PI3K/AKT/mTOR axis is also inhibited by metformin (AMPK-independent manner). Although increased nutrients, such as amino acids and glucose, activate proliferation via mTOR activation, lack of metabolites inhibits cellular growth and division (not shown). GDP Guanosine-5′-diphosphate, GLUT glucose transporter, GTP Guanosine-5′-triphosphate, mTOR mammalian target of rapamycin