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 proinf lammatory 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.

Ras transformation requires metabolic control by 6-phosphofructo-2-kinase

“…However, this effect was minuscule relative to the large decrease in the F2,6BP Ras and 6-phosphofructo-2-kinase S Telang et al of F2,6BP during immortalization may reflect a negative feedback compensation in response to increased flux at PFK-1, changes in F2,6BP stability in situ (e.g., low intracellular pH) or increased conversion of F2,6BP into F6P for glycolytic utilization. Nevertheless, these data run counter to the widely held assumption that the intracellular F2,6BP concentration directly corresponds to and possibly sets the proliferative rate (Van Schaftingen et al, 1981;Hue and Rousseau, 1993;Chesney et al, 1999). We observed marked differences in glucose metabolism between primary mouse fibroblasts and human bronchial epithelial cells during ras-transformation.…”

“…The PFKFB3 gene encodes for the inducible PFK2/FBPase (Chesney et al, 1999;Atsumi et al, 2002;Mahlknecht et al, 2003), which is rapidly induced by inflammatory stimuli (Chesney et al, 1999) and hypoxia (Minchenko et al, 2002;Minchenko et al, 2004) and has also been termed placental PFK2 (Sakai et al, 1996;Sakakibara et al, 1999), ubiquitous PFK2 (Manzano et al, 1998;Kessler and Eschrich, 2001;Navarro-Sabate et al, 2001) and PGR1 (Hamilton et al, 1997)). The PFKFB3 protein product was recently documented to be overexpressed in the neoplastic cells of human solid tumors, including lung, breast, prostate and colon tumors and to display minimal phosphatase activity (kinase:phosphatase ratio 740:1), suggesting a constitutively pro-glycolytic activity (Sakakibara et al, 1997;Chesney et al, 1999;Chesney and Bucala, 2001;Atsumi et al, 2002).…”

Profiling of the yak skeletal muscle tissue gene expression and comparison with the domestic cattle by genome array

“…PFKFB3 has a high ratio of kinase and phosphatase, which maintain a higher level of fructose-2,6-diphosphate in the body and speed up the glycolysis (Sakakibara et al, 1997;Chesney et al, 1999). PFKFB4 encode the isoenzyme of 6-phosphofructo-2-kinase/ fructose-2, 6-biphosphatase.…”

L’effet Warburg

“…SYNTHÈSE REVUES 3' non traduite du brin (3'UTR) [7]. Ce motif est généralement retrouvé dans des gènes de réponse précoce qui codent pour des protéines, comme des cytokines inflammatoires ou des proto-oncogènes, qui répondent à des stimulus extracellulaires, comme des facteurs de croissance ou des neurotransmetteurs.…”