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Zancan P.,Laboratorio Of Oncobiologia Molecular Labomol | Sola-Penna M.,Laboratorio Of Enzimologia E Controle Do Metabolismo Labecom | Furtado C.M.,Laboratorio Of Oncobiologia Molecular Labomol | Da Silva D.,Laboratorio Of Enzimologia E Controle Do Metabolismo Labecom
Molecular Genetics and Metabolism | Year: 2010

Cancer cells are characterized by increased aerobic glycolysis, which correlates with a negative prognosis. Although this correlation is well known, the mechanism of the elevated rate of glycolysis in cancer and the role of glycolytic enzymes have yet to be determined. The present work aims to evaluate the activity of the major enzymes that regulate glycolysis in breast cancer cell lines of varying aggressiveness. MCF10A, MCF-7 and MDA-mb-231 are human breast-derived cell lines with non-tumorigenic, tumorigenic and metastatic profiles, respectively. These cell lines have increasing degrees of glycolytic efficiency, i.e., lactate produced per glucose consumed, corresponding to their metastatic potential. Although, there are no differences in phosphofructokinase (PFK) or pyruvate kinase (PK) activities, the activity of hexokinase (HK) activity is higher in both tumorigenic cell lines compared to MCF10A cells. No difference in HK activity is observed between MCF-7 and MDA-mb-231 cells, suggesting that the difference in their glycolytic efficiency could not be attributed to this enzyme. However, we find that expression of the PFK-L isoform directly and strongly correlates with aggressiveness and glycolytic efficiency in these cell lines. Thus, we conclude that glycolytic efficiency, which is important for the survival of cancer cells, depends primarily on the preferential expression of PFK-L over the M and P isoforms. © 2010 Elsevier Inc. Source


Da Silva D.,Laboratorio Of Enzimologia E Controle Do Metabolismo Labecom | Ausina P.,Laboratorio Of Enzimologia E Controle Do Metabolismo Labecom | Alencar E.M.,Laboratorio Of Enzimologia E Controle Do Metabolismo Labecom | Coelho W.S.,Laboratorio Of Enzimologia E Controle Do Metabolismo Labecom | And 2 more authors.
IUBMB Life | Year: 2012

Diabetes mellitus is characterized by hyperglycemia and its associated complications, including cardiomyopathy. Metformin, in addition to lowering blood glucose levels, provides cardioprotection for diabetic subjects. Glycolysis is essential to cardiac metabolism and its reduction may contribute to diabetic cardiomyopathy. Hexokinase (HK) and phosphofructokinase (PFK), rate-limiting enzymes of glycolysis, are downregulated in cardiac muscle from diabetic subjects, playing a central role on the decreased glucose utilization in the heart of diabetic subjects. Thus, the aim of this study was to determine whether metformin modulates heart HK and PFK from diabetic mice. Diabetes was induced by streptozotocin injection on male Swiss mice, which were treated for three consecutive days with 250 mg/kg metformin before evaluating HK and PFK activity, expression, and intracellular distribution on the heart of these subjects. We show that metformin abrogates the downregulation of HK and PFK in the heart of streptozotocin-induced diabetic mice. This effect is not correlated to alteration on the enzymes' transcription and expression. However, the intracellular distribution of both enzymes is altered in diabetic hearts that show increased activity of the soluble fraction when compared to the particulate fraction. Moreover, this pattern is reversed upon the treatment with metformin, which is correlated with the effects of the drug on the enzymes activity. Altogether, our results support evidences that metformin alter the intracellular localization of HK and PFK augmenting glucose utilization by diabetic hearts and, thus, conferring cardiac protection to diabetic subjects. © 2012 IUBMB IUBMB Life, 64(9): 766-774, 2012 Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc. Source


Silva D.D.,Laboratorio Of Enzimologia E Controle Do Metabolismo Labecom | Zancan P.,Laboratorio Of Oncobiologia Molecular Labomol | Coelho W.S.,Laboratorio Of Enzimologia E Controle Do Metabolismo Labecom | Gomez L.S.,Laboratorio Of Enzimologia E Controle Do Metabolismo Labecom | Sola-Penna M.,Laboratorio Of Enzimologia E Controle Do Metabolismo Labecom
Archives of Biochemistry and Biophysics | Year: 2010

The present work describes the effects of metformin on hexokinase (HK) and phosphofructokinase (PFK) activities and localization in different tissues from streptozotocin-induced diabetic mice. Diabetic mice present lower HK and PFK activities (50%) in skeletal muscle, liver and adipose tissue, as compared with control (P<0.05). Treatment with 250. mg/kg metformin reverses this pattern of enzyme inhibition with concomitant reversal of hyperglycemia and hypolactacidemia. Furthermore, the treatment increases the cytoskeleton-associated PFK activity in skeletal muscle; this activity has been described as an important mechanism for the enzyme activation. This effect might be due to the increased phosphorylation of serine residues in the enzyme, a modification which has been described to increase the interaction of PFK with f-actin. The current work supports the hypothesis that metformin hypoglycemic effects involve the activation of glycolysis through its regulatory enzymes, which may be potential targets for the development of new hypoglycemic drugs. © 2010 Elsevier Inc. Source

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