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THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 288, NO. 50, pp. 36020 ?6028, December 13, 2013 ?2013 by The American Society for Biochemistry and Molecular Biology, Inc. Published within the U.S.A.Improved Concentrations of Fructose 2,6-Bisphosphate Contribute towards the Warburg Impact in Phosphatase and Tensin Homolog (PTEN)-deficient Cells*SReceived for publication, August 14, 2013, and in revised form, October 20, 2013 Published, JBC Papers in Press, October 29, 2013, DOI ten.1074/jbc.M113.Luc Cordero-Espinoza and Thilo Hagen1 From the Division of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, SingaporeBackground: PTEN deficiency leads to increased glycolytic flux characteristic of cancer cells. Outcomes: PTEN-deficient cells have higher concentrations of fructose two,6-bisphosphate due to protein stabilization of PFKFB3 that final results from impaired APC/C-Cdh1-dependent degradation. Conclusion: Elevated fructose two,6-bisphosphate concentrations contribute towards the improved prices of glycolysis and proliferation in PTEN-deficient cells. Significance: Fructose two,6-bisphosphate may be a important mediator of tumorigenesis in PTEN-deficient cells. As opposed to typical differentiated cells, tumor cells metabolize glucose through glycolysis under aerobic conditions, a hallmark of cancer referred to as the Warburg effect. Cells lacking the frequently mutated tumor suppressor PTEN exhibit a glycolytic phenotype reminiscent from the Warburg impact.Methyl 1H-1,2,3-triazole-4-carboxylate structure This has been traditionally attributed towards the hyperactivation of PI3K/Akt signaling that outcomes from PTEN loss.Bis(4-methoxybenzyl)amine site Right here, we propose a novel mechanism whereby the loss of PTEN negatively impacts the activity from the E3 ligase APC/C-Cdh1, resulting within the stabilization from the enzyme PFKFB3 and enhanced synthesis of its solution fructose 2,6-bisphosphate (F2,6P2). We found that when compared with wild-type cells, PTEN knock-out mouse embryonic fibroblasts (PTEN KO MEF) have 2?-fold larger concentrations of F2,6P2, by far the most potent allosteric activator with the glycolytic enzyme phosphofructokinase-1 (PFK-1).PMID:23962101 Reintroduction of either wild-type or phosphatase mutant PTEN within the PTEN KO cells efficiently lowers F2,6P2 towards the wild-type levels and reduces their lactate production. PTEN KO cells have been identified to possess higher protein levels of PFKFB3, which straight contribute for the enhanced concentrations of F2,6P2. PTEN enhances interaction among PFKFB3 and Cdh1, and overexpression of Cdh1 down-regulates the PFKFB3 protein level in wild-type, but not in PTEN-deficient cells. Importantly, we found that the degradation of endogenous PFKFB3 in PTEN KO cells occurs at a slower rate than in wild-type cells. Our final results recommend a vital part for F2,6P2 in the metabolic reprogramming of PTEN-deficient cells which has vital consequences for cell proliferation.To meet their bioenergetic requirements, differentiated cells usually metabolize glucose by way of oxidative phosphorylation as a way of maximizing ATP production. In contrast, cancer cellsare characterized by high prices of glycolysis and metabolize glucose into lactate even inside the presence of oxygen, a phenomenon known as the “Warburg effect” or “aerobic glycolysis” (1). Upregulation of glycolysis is proposed to endow cancer cells with various selective advantages, in particular the incorporation of nutrients into biomass to sustain high prices of proliferation (2, three).
