AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the alpha 1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPK alpha in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1 alpha (HIF-1 alpha), as silencing HIF-1 alpha reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPK alpha signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation.