Phenformin inhibits tumor growth through a Complex I-independent redox/corepressor axis

The antidiabetic drug phenformin displays potent anticancer activity in different tumors but its mechanism of action remains elusive. Using Shh Medulloblastoma as model, we show here that at the clinically relevant concentrations phenformin elicits a significant therapeutic effect through a redox-dependent, but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerol-phosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between the corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Since ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy.