Carbohydrate Metabolism and Neoplasia: New Perspectives for Diagnosis and Therapy

Eigenbrodt, Erich; Gerbracht, U.; Mazurek, Sybille; Presek, Peter; Friis, Robert R.

doi:10.1016/b978-0-12-564499-0.50014-6

Cited by 32 publications

(72 citation statements)

References 473 publications

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“…Data from former reports suggest that there are many factors contributing to the origin of aerobic glycolysis (2). The altered control of glycolysis by expression of certain isoenzymes is one important factor (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Furthermore, the glycerol 3-phosphate shuttle and the malate-aspartate shuttle are altered in such a way that transport of cytosolic hydrogen into the mitochondria is reduced, requiring tumor cells to reoxidize NADH cytosolically by lactate dehydrogenase (13)(14)(15).…”

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confidence: 99%

“…Observations on aerobic glycolysis in tumor cells prompted Warburg (1) to postulate an altered respiratory function leading to an increased glycolytic capacity and a high rate of lactate formation from glucose in the presence of oxygen. Data from former reports suggest that there are many factors contributing to the origin of aerobic glycolysis (2). The altered control of glycolysis by expression of certain isoenzymes is one important factor (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

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confidence: 99%

“…Therefore, high glycolytic activity ensures the survival and the migration of tumor cells in hypoxic areas (2,26,27). The main role of the glutaminolytic pathway is the generation of energy (2,25). However, a high glycolytic rate is not always linked to cell proliferation or tumor formation.…”

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confidence: 99%

“…The conversion of glutamine to lactate is called, in analogy to glycolysis, glutaminolysis (25). In tumor cells the glycolytic capacity can be so great that all of the cell's energy requirements are derived from glycolysis (2,26). Therefore, high glycolytic activity ensures the survival and the migration of tumor cells in hypoxic areas (2,26,27).…”

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confidence: 99%

“…In tumor cells the glycolytic capacity can be so great that all of the cell's energy requirements are derived from glycolysis (2,26). Therefore, high glycolytic activity ensures the survival and the migration of tumor cells in hypoxic areas (2,26,27). The main role of the glutaminolytic pathway is the generation of energy (2,25).…”

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confidence: 99%

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Effect of Extracellular AMP on Cell Proliferation and Metabolism of Breast Cancer Cell Lines with High and Low Glycolytic Rates

Mazurek

Michel²,

Eigenbrodt

1997

Journal of Biological Chemistry

101

107

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In differentiated tissues, such as muscle and brain, increased adenosine monophosphate (AMP) levels stimulate glycolytic flux rates. In the breast cancer cell line MCF-7, which characteristically has a constantly high glycolytic flux rate, AMP induces a strong inhibition of glycolysis. The human breast cancer cell line MDA-MB-453, on the other hand, is characterized by a more differentiated metabolic phenotype. MDA-MB-453 cells have a lower glycolytic flux rate and higher pyruvate consumption than MCF-7 cells. In addition, they have an active glycerol 3-phosphate shuttle. AMP inhibits cell proliferation as well as NAD and NADH synthesis in both MCF-7 and MDA-MB-453 cells. However, in MDA-MB-453 cells glycolysis is slightly activated by AMP. This disparate response of glycolytic flux rate to AMP treatment is presumably caused by the fact that the reduced NAD and NADH levels in AMP-treated MDA-MB-453 cells reduce lactate dehydrogenase but not cytosolic glycerol-3-phosphate dehydrogenase reaction. Due to the different enzymatic complement in MCF-7 cells, proliferation is inhibited under glucose starvation, whereas MDA-MB-453 cells grow under these conditions. The inhibition of cell proliferation correlates with a reduction in glycolytic carbon flow to synthetic processes and a decrease in phosphotyrosine content of several proteins in both cell lines.Both proliferating cells and tumor cells maintain a high glycolytic rate even under aerobic conditions, a process referred to as aerobic glycolysis. Observations on aerobic glycolysis in tumor cells prompted Warburg (1) to postulate an altered respiratory function leading to an increased glycolytic capacity and a high rate of lactate formation from glucose in the presence of oxygen. Data from former reports suggest that there are many factors contributing to the origin of aerobic glycolysis (2). The altered control of glycolysis by expression of certain isoenzymes is one important factor (2-12). Furthermore, the glycerol 3-phosphate shuttle and the malate-aspartate shuttle are altered in such a way that transport of cytosolic hydrogen into the mitochondria is reduced, requiring tumor cells to reoxidize NADH cytosolically by lactate dehydrogenase (13-15). Additionally, oxidation of pyruvate is reduced in favor of glutamine oxidation (16 -25). Due to the expression of the mitochondrial, NAD-dependent malate decarboxylase, malate is converted to pyruvate and lactate (22)(23)(24). The conversion of glutamine to lactate is called, in analogy to glycolysis, glutaminolysis (25). In tumor cells the glycolytic capacity can be so great that all of the cell's energy requirements are derived from glycolysis (2, 26). Therefore, high glycolytic activity ensures the survival and the migration of tumor cells in hypoxic areas (2,26,27). The main role of the glutaminolytic pathway is the generation of energy (2, 25). However, a high glycolytic rate is not always linked to cell proliferation or tumor formation. There are several cell lines that are able to grow in a medium with 5 mM gala...

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Effect of Extracellular AMP on Cell Proliferation and Metabolism of Breast Cancer Cell Lines with High and Low Glycolytic Rates

Mazurek

Michel²,

Eigenbrodt

1997

Journal of Biological Chemistry

101

107

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Studies on associations of glycolytic and glutaminolytic enzymes in MCF-7 cells: Role of P36

et al. 1996

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Isoelectric focusing of MCF-7 cell extracts revealed an association of the glycolytic enzymes glyceraldehyde 3-phosphate-dehydrogenase, phosphoglycerate kinase, enolase, and pyruvate kinase. This complex between the glycolytic enzymes is sensitive to RNase. p36 could not be detected within this association of glycolytic enzymes; however an association of p36 with a specific form of malate dehydrogenase was found. In MCF-7 cells three forms of malate dehydrogenase can be detected by isoelectric focusing: the mitochondrial form with an isoelectric point between 8.9 and 9.5, the cytosolic form with pl 5.0, and a p36-associated form with pl 7.8. The mitochondrial form comprises the mature mitochondrial isoenzyme (pl 9.5) and its precursor form (pl 8.9). Refocusing of the pl 7.8 form of malate dehydrogenase also gave rise to the mitochondrial isoenzyme. Thus, the pl 7.8 form of malate dehydrogenase is actually the mitochondrial isoenzyme retained in the cytosol by the association with p36. Addition of fructose 1,6-bisphosphate to the initial focusing column induced a quantitative shift of the pl 7.8 form of malate dehydrogenase to the mitochondrial forms (pl 8.9 and 9.5). In MCF-7 cells p36 is not phosphorylated in tyrosine. Kinetic measurements revealed that the pl 7.8 form of malate dehydrogenase has the lowest affinity for NADH. Compared to both mitochondrial forms the cytosolic isoenzyme has a high capacity when measured in the NAD --> NADH direction (malate --> oxaloacetate direction). The association of p36 with the mitochondrial isoenzyme may favor the flow of hydrogen from the cytosol into the mitochondria. Inhibition of cell proliferation by AMP which leads to an inhibition of glycolysis has no effect on complex formation by glycolytic and glutaminolytic enzymes in MCF-7 cells. AMP treatment leads to an activation of malate dehydrogenase, which correlates with the increase of pyruvate and the decrease of lactate levels, but has no effect on the distribution of the various malate dehydrogenase forms.

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Alterations in the glycolytic and glutaminolytic pathways after malignant transformation of rat liver oval cells

et al. 1999

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Oval cells are liver epithelial cells that proliferate during the early stages of hepatocarcinogenesis induced by a variety of chemicals. The oval cell lines OC/CDE 6 and OC/CDE 22 have been established in our laboratory at two time points (6 and 22 weeks) of the carcinogenic process and have been malignantly transformed by different procedures. During the transformation process, the glycolytic and glutaminolytic flux rates were consistently up-regulated and this process was accompanied by an overproportional increase in the activities of cytosolic hexokinase and 6-phosphogluconate dehydrogenase. In transformed oval cells, a strong correlation between the glycolytic flux rate and glutamine consumption as well as glutamate production was observed. Furthermore, the transport of glycolytic hydrogen, produced by the glyceraldehyde 3-phosphate dehydrogenase-catalyzed reaction, from the cytosol into the mitochondria by means of the malate-aspartate shuttle was enhanced, this being due to alterations in the activities of malate dehydrogenase and glutamate oxaloacetate transaminase. The up-regulation of the glycolytic hydrogen transport and the alterations in the glycolytic enzyme complex led to an enhanced pyruvate production at high glycolytic flux rates. Taken together, our data are further proof that a special metabolic feature (increased glycolysis and glutaminolysis) is characteristic for tumor cells and that the mechanisms by which this metabolic state is induced can be totally different.

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Carbohydrate Metabolism and Neoplasia: New Perspectives for Diagnosis and Therapy

Cited by 32 publications

References 473 publications

Effect of Extracellular AMP on Cell Proliferation and Metabolism of Breast Cancer Cell Lines with High and Low Glycolytic Rates

Effect of Extracellular AMP on Cell Proliferation and Metabolism of Breast Cancer Cell Lines with High and Low Glycolytic Rates

Studies on associations of glycolytic and glutaminolytic enzymes in MCF-7 cells: Role of P36

Alterations in the glycolytic and glutaminolytic pathways after malignant transformation of rat liver oval cells

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