High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers.
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.
Atsumi
Toshiya
T
The Picower Institute for Medical Research NY, Manhasset, New York 10030, USA.
Chesney
Jason
J
Metz
Christine
C
Leng
Lin
L
Donnelly
Seamas
S
Makita
Zenji
Z
Mitchell
Robert
R
Bucala
Richard
R
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
D004273:DNA, Neoplasm; D011506:Proteins; D012333:RNA, Messenger; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2