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

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 regu lator 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 depend s 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 pre sence of multiple copies of the AUUUA mRNA instability motif in its 3'-untr anslated 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 express ion decreased the intracellular level of 5-phosphoribosyl-1-pyrophosphate, a product of the pentose phosphate pathway and an important precursor for n ucleic acid biosynthesis. These studies identify a regulatory isoenzyme tha t may be essential for tumor growth and provide an explanation for long-sta nding observations concerning the apparent coupling of enhanced glycolysis and cell proliferation.