6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for p53-null cancer cells
| Autor: | Ros, S, Flöter, J, Kaymak, I, Da Costa, C, Houddane, A, Dubuis, S, Griffiths, B, Mitter, R, Walz, S, Blake, S, Behrens, A, Brindle, KM, Zamboni, N, Rider, MH, Schulze, A |
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| Přispěvatelé: | Brindle, Kevin [0000-0003-3883-6287], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
Mice Knockout Lung Neoplasms Phosphofructokinase-2 Mice Nude Apoptosis Fructose Prognosis Xenograft Model Antitumor Assays Pentose Phosphate Pathway Survival Rate Mice Glucose Colonic Neoplasms Biomarkers Tumor Tumor Cells Cultured Animals Humans Neoplasm Invasiveness Tumor Suppressor Protein p53 Glycolysis Oxidation-Reduction Cell Proliferation Neoplasm Staging |
| DOI: | 10.17863/cam.7717 |
| Popis: | The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) controls metabolic flux through allosteric regulation of glycolysis. Here we show that p53 regulates the expression of PFKFB4 and that p53-deficient cancer cells are highly dependent on the function of this enzyme. We found that p53 downregulates PFKFB4 expression by binding to its promoter and mediating transcriptional repression via histone deacetylases. Depletion of PFKFB4 from p53-deficient cancer cells increased 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 was also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53-deficient cancer cells. Moreover, depletion of PFKFB4-attenuated cellular biosynthetic activity and resulted in the accumulation of reactive oxygen species and cell death in the absence of p53. Finally, silencing of PFKFB4-induced apoptosis in p53-deficient cancer cells in vivo and interfered with tumour growth. These results demonstrate that PFKFB4 is essential to support anabolic metabolism in p53-deficient cancer cells and suggest that inhibition of PFKFB4 could be an effective strategy for cancer treatment. |
| Databáze: | OpenAIRE |
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