Metformin: a diabetes drug for cancer, or a cancer drug for diabetics?

Clinical evidence that diabetics receiving metformin have a reduced lifetime incidence of cancer has sparked keen interest in the biguanide class of compounds as potential anticancer agents. In Journal of Clinical Oncology, Bonnani et al report on how presurgical treatment of patients with breast cancer with metformin affects the proliferation of their tumor cells. Their results highlight both the complexities and possibilities of metformin in breast cancer and, importantly, provide a rationale for moving to large-scale clinical trials to identify which patients are likely to benefit. The precise molecular target of metformin is unknown, but it acts to inhibit complex I of the mitochondrial electron transport chain to block oxidative respiration (Fig 1). This results in increased cellular AMP-to-ATP ratios and activates the AMP-activated protein kinase (AMPK). AMPK coordinates the activity of a plethora of key metabolic and growth pathways that together act to restore cellular energy balance. For example, it increases GLUT1 expression to promote glucose uptake and phosphorylates phosphofructokinase-2 to promote energy generation through increased glycolysis. Conversely, it phosphorylates proteins such as TSC2 and Raptor (components of the mammalian target of rapamycin [mTOR] cascade) to inhibit protein synthesis, and it phosphorylates acetyl-CoA carboxylase to inhibit lipid synthesis, thereby suppressing processes that consume energy. The first definitive link between AMPK and cancer came from the discovery that LKB1, the protein kinase that is mutated in the familial cancer disorder Peutz-Jeghers syndrome, is the major upstream activator of AMPK. The link between LKB1 and AMPK was most clearly demonstrated in a seminal study where LKB1 was deleted in mouse livers. Critically, this prevented liver-specific activation of AMPK and made the mice refractory to the glucose-lowering effects of metformin, showing that the primary mechanism of action of metformin is through its ability to activate AMPK. It was subsequently shown that metformin and phenformin, a related biguanide, inhibited the development of spontaneous tumors in PTEN-null mice and that metformin blocked human breast cancer xenograft growth in immunocompromised mice. Metformin directly blocks breast cancer cell growth by inhibiting the Raptor/mTOR (mTORC1) complex, thereby suppressing protein synthesis downstream of pathways such as the insulin cascade. Insulin receptors activate mTORC1 through the protein kinase AKT (Fig 2), which phosphorylates and inhibits TSC2, allowing the small G-protein RHEB to activate mTORC1 and consequently another protein kinase, S6K1, to drive protein synthesis. Critically, AMPK inhibits mTORC1 by phosphorylating and activating TSC2 to inhibit RHEB and also by phosphorylating Raptor directly (Fig 2). However, emerging data suggest that metformin can inhibit mTOR in an AMPK-independent manner; an important caveat is that metformin inhibits cell growth in vitro in the millimolar range, and these concentrations cannot be achieved in patients. This is probably because metformin enters cells through the organic cation transporters OCT1 and OCT2, which are highly expressed in liver and adipose cells but are generally low in other cells. How then, does metformin inhibit the growth of tumors in mouse modelsofcancerandhumans? Toanswer this,weneedtoremember that metformin was developed to relieve the deleterious physical effects of metabolic syndromes and that obesity and diabetes are both associated with elevated risk of breast cancer. Thus, the key contribution of metformin to reducing breast cancer risk could be its ability to reduce AMP ATP