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Curr Opin Clin Nutr Metab Care · Sep 2006
Review6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and tumor cell glycolysis.
- Jason Chesney.
- Molecular Targets Group, Medical Oncology, James Graham Brown Cancer Center, University of Louisville, Kentucky 40202, USA. jason.chesney@louisville.edu
- Curr Opin Clin Nutr Metab Care. 2006 Sep 1; 9 (5): 535-9.
Purpose Of ReviewNeoplastic cells metabolize abundant glucose relative to normal cells in order to satisfy the increased energetic and anabolic needs of the transformed state. This review will summarize the requirement of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases for the regulation of glycolysis in cancer cells and their potential utility as targets for the development of antineoplastic agents.Recent FindingsThe steady-state concentration of fructose-2,6-bisphosphate controls the overall rate of glycolysis by allosterically activating a rate-limiting enzyme, 6-phosphofructo-1-kinase. The intracellular concentration of fructose-2,6-bisphosphate is controlled by a family of bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases that are encoded by four independent genes (PFKFB1-4). The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase encoded by the PFKFB3 gene has the highest kinase:phosphatase activity ratio of the four enzymes and thus contributes significantly to the synthesis of fructose-2,6-bisphosphate. PFKFB3 is activated by mitogenic, inflammatory and hypoxic stimuli, and was recently found to be constitutively expressed by several human leukemias and solid tumor cells. By setting the intracellular fructose-2,6-bisphosphate concentration, PFKFB3 controls glycolytic flux to lactate and the nonoxidative pentose shunt, and is selectively required for the tumorigenic growth of ras-transformed cells.SummaryThese findings demonstrate a key role for the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in neoplastic transformation and provide rationale for the development of agents that selectively inhibit the PFKFB3 enzyme as antineoplastic agents.
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