Direct and indirect effects of metformin on cancer. Metformin activates AMPK leading to stabilization of TSC2 and inhibition of mTORC1 signaling and protein synthesis. Metformin can also directly target mTOR independently of AMPK and TSC2. Systemically, metformin sensitizes tissues to insulin, reduces hepatic gluconeogenesis, and lowers circulating insulin levels, indirectly reducing receptor tyrosine kinase activation and PI3K signaling. AMPK = AMP-activated protein kinase; 4E-BP1 = eukaryotic initiation factor 4E-binding protein-1; LKB1 = liver kinase B1; mTORC1 = mammalian target of rapamycin complex 1; PI3K = phosphatidylinositol-3-kinase; PKB/Akt = protein kinase B; PTEN = phosphatase and tensin homologue deleted on chromosome 10; Rheb = Ras homologue enriched in brain; S6K = ribosomal protein S6 kinase; TSC2 = tuberous sclerosis complex 2.