Figure 1.

Metformin affects cancer cells both directly and indirectly. It activates AMP-activated protein kinase (AMPK), which leads, among other things, to inhibition of mammalian target of rapamycin (mTOR). It also sensitizes tissues to insulin, reduces hepatic gluconeogenesis and decreases circulating insulin levels. This leads indirectly to reduced phosphatidylinositol-3-kinase (PI3K) signaling. In addition, metformin deactivates the downstream signaling molecules ERK and STAT3, which have effects on cell growth and apoptosis (8,12,13). IGF-1, insulin-like growth factor 1; ACC, acetyl-CoA carboxylase; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; p53, tumor protein p53; AKT, serine/theonine-specific protein kinase; ERK, extracellular signal-regulated kinase; TSC2, tuberous sclerosis complex 2; STAT3, signal transducer and activator of transcription 3.