the key role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in neoplastic transformation provides a rational for the development of agents that selectively inhibit the PFKFB3 enzyme as antineoplastic agents
bifunctional 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 mRNA expression is greater in metastatic prostate cancer compared with primary tumors
in colonic and bladder cancer cells, additive growth inhibitory effects are seen with phenformin and with an inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3. The increased acidification of the culture medium and glucose uptake caused by phenformin is blocked by combined treatment with PFKFB3 inhibitors
tumor suppressor p53 regulates the expression of PFKFB4 and p53-deficient cancer cells are highly dependent on the function of the enzyme. Depletion of PFKFB4 from p53-deficient cancer cells increases levels of the allosteric regulator fructose-2,6-bisphosphate, leading to increased glycolytic activity but decreased routing of metabolites through the oxidative arm of the pentose-phosphate pathway. PFKFB4 is also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53-deficient cancer cells. Depletion of PFKFB4-attenuated cellular biosynthetic activity and results in the accumulation of reactive oxygen species and cell death in the absence of p53. Silencing of PFKFB4-induces apoptosis in p53-deficient cancer cells in vivo and interferes with tumor growth