An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect.

Abstract

Cancer cells maintain a high glycolytic rate even in the presence of oxygen, a phenomenon first described over 70 years ago and known historically as the Warburg effect. Fructose 2,6-bisphosphate is a powerful allosteric regulator of glycolysis that acts to stimulate the activity of 6-phosphofructo-1-kinase (PFK-1), the most important control point in mammalian glycolysis. The steady state concentration of fructose 2,6-bisphosphate in turn depends on the activity of the enzyme 6-phosphofructo-2-kinase (PFK-2)/fructose-2, 6-bisphosphatase, which is expressed in several tissue-specific isoforms. We report herein the identification of a gene product for this enzyme that is induced by proinflammatory stimuli and which is distinguished by the presence of multiple copies of the AUUUA mRNA instability motif in its 3'-untranslated end. This inducible gene for PFK-2 is expressed constitutively in several human cancer cell lines and was found to be required for tumor cell growth in vitro and in vivo. Inhibition of inducible PFK-2 protein expression decreased the intracellular level of 5-phosphoribosyl-1-pyrophosphate, a product of the pentose phosphate pathway and an important precursor for nucleic acid biosynthesis. These studies identify a regulatory isoenzyme that may be essential for tumor growth and provide an explanation for long-standing observations concerning the apparent coupling of enhanced glycolysis and cell proliferation.

• Authors: J Chesney, R Mitchell, F Benigni, M Bacher, L Spiegel, Y Al-Abed, J H Han, C Metz, R Bucala
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 96 Issue 6 Pg. 3047-52 (Mar 16 1999) ISSN: 0027-8424 [Print] United States
• PMID: 10077634 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• RNA, Messenger
• Phosphotransferases (Alcohol Group Acceptor)
• Phosphofructokinase-2

Topics

• 3' Untranslated Regions (genetics)
• Allosteric Regulation
• Amino Acid Sequence
• Base Sequence
• Cell Division
• Cell Transformation, Neoplastic
• Cloning, Molecular
• Gene Expression Regulation, Neoplastic
• Glycolysis
• Humans
• Molecular Sequence Data
• Neoplasms (genetics, metabolism, pathology)
• Phosphofructokinase-2
• Phosphotransferases (Alcohol Group Acceptor) (genetics, metabolism)
• RNA, Messenger (analysis, genetics)
• Sequence Alignment
• Tumor Cells, Cultured