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High Expression of Inducible 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase (iPFK-2; PFKFB3) in Human Cancers¹

The Picower Institute for Medical Research NY, Manhasset, New York 10030 [T. A., J. C., C. M., S. D., R. M.]; Kurume University School of Medicine, Kurume, Japan [Z. M.]; Division of Immunology, Weill Medical College of Cornell University, New York, New York 10021 [J. C.]; and Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8031 [L. L., R. B.]

Tumor cells maintain an especially high glycolytic rate to supply the anabolic precursors essential for de novo nucleotide synthesis. We recently cloned an inducible isozyme of 6-phosphofructo-2 kinase (iPFK-2) that bears an oncogene-like regulatory element in its mRNA and functions to produce fructose-2,6-bisphosphate, which is a powerful allosteric activator of glycolysis. Rapidly proliferating cancer cells constitutively express iPFK-2 in vitro, and inhibition of iPFK-2 expression decreases tumor growth in experimental animal models. We report herein that the expression of iPFK-2 mRNA and protein, as assessed by in situ hybridization and immunohistochemistry, is increased in many human cancers when compared with corresponding normal tissues. In particular, iPFK-2 expression was found to be markedly elevated in multiple aggressive primary neoplasms, including colon, breast, ovarian, and thyroid carcinomas. iPFK-2 mRNA and protein expression were induced by hypoxia in cultured human colon adenocarcinoma cells, and an examination of normal lung fibroblasts showed that iPFK-2 and fructose-2,6-bisphosphate levels increased specifically during the S phase of the cell cycle. These data indicate that iPFK-2 is abundantly expressed in human tumors in situ and may serve as an essential regulator of glycolysis during cell cycle progression and growth in an hypoxic microenvironment.

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