Up-regulation of glycolysis is proposed to endow cancer cells withseveral selective advantages, in particular the incorporation ofnutrients into biomass to sustain high rates of proliferation (2,3). Deregulation of certain cancer-related genes has been linkedto the acquisition of the glycolytic phenotype (4). The phospha-tase and tensin homolog, PTEN,2is a tumor suppressor mostwell known for its ability to oppose the PI3K/Akt signalingpathway through the dephosphorylation of phosphatidylino

To meet their bioenergetic requirements, differentiated cellstend to metabolize glucose via oxidative phosphorylation as away of maximizin

EN knock-out mouseembryonic fibroblasts (PTEN KO MEF) have 2–3-fold higherconcentrations of F2,6P2, the most potent allosteric activator ofthe glycolytic enzyme phosphofructokinase-1 (PFK-1)

This has beentraditionally attributed to the hyperactivation of PI3K/Akt sig-naling that results from PTEN loss. Here, we propose a novelmechanism whereby the loss of PTEN negatively affects theactivity of the E3 ligase APC/C-Cdh1, resulting in the stabiliza-tion of the enzyme PFKFB3 and increased synthesis of its prod-uct fructose 2,6-bisphosphate (F2,6P2)

Unlike normal differentiated cells, tumor cells metabolizeglucose via glycolysis under aerobic conditions, a hallmark ofcancer known as the Warburg effect

Our results suggest animportant role for F2,6P2in the metabolic reprogramming ofPTEN-deficient cells that has important consequences forcell proliferation.