title: High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers.
abstract: 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.
authors.affiliation: The Picower Institute for Medical Research NY, Manhasset, New York 10030, USA.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Atsumi
authors.forename: Jason
authors.initials: J
authors.lastname: Chesney
authors.forename: Christine
authors.initials: C
authors.lastname: Metz
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Seamas
authors.initials: S
authors.lastname: Donnelly
authors.forename: Zenji
authors.initials: Z
authors.lastname: Makita
authors.forename: Robert
authors.initials: R
authors.lastname: Mitchell
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D015687:Cell Hypoxia; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D025481:Phosphofructokinase-2 / Q000096:biosynthesis* / Q000235:genetics; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016196:S Phase / Q000502:physiology; D015854:Up-Regulation
chemical_list: D004273:DNA, Neoplasm; D011506:Proteins; D012333:RNA, Messenger; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2