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Systems Biology of Metabolic and Signaling Networks pp 213–239Cite as

Systems Biology Approaches to Cancer Energy Metabolism

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Part of the book series: Springer Series in Biophysics ((BIOPHYSICS,volume 16))

Abstract

Application of Systems Biology approaches to energy metabolism of cancer cells help in the understanding of their controlling and regulatory mechanisms and identification of new drug targets. Our group built and validated a kinetic model of tumor glycolysis based on the experimental determination of all the enzyme/transporter kinetic parameters, metabolite concentrations, and fluxes in tumor cells. Model predictions enabled to understand how glycolysis is controlled and allowed identification of the main controlling steps which can be the most promising therapeutic targets. In this chapter, the model was extended to determine the contribution on the pathway function of the expression of different glycolytic isoforms displaying different catalytic properties, a feature commonly observed in tumor cells subjected to hypoxia. Model predictions now indicated that, by fully changing the glucose transporter (GLUT), hexokinase (HK), or both, from low- to high affinity isoforms, the glycolytic flux can be increased (GLUT+HK>GLUT>>HK); however, this concurred with a marked deregulation of the adenine nucleotides concentration. To gradually increase glycolytic flux with no alteration of adenine nucleotides homeostasis, which is closer to the physiological response of tumor cells, the model indicated that simultaneous expression in different ratios of GLUT and HK isoforms with different affinities should be accomplished. Mitochondrial metabolism is also active and essential for cancer cells. Therefore, a cancer energy metabolism model, including glycolysis and oxidative phosphorylation (Krebs cycle, respiratory chain, Pi/ADP transport, ATP synthase), should identify the most appropriate sites for successful multi-target therapies.

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Abbreviations

ALDO:

Aldolase

DHAP:

Dihydroxyacetone phosphate

ENO:

Enolase

Ery4P:

Erythrose-4-phosphate

FBP:

Fructose-1,6-bisphosphate

F6P:

Fructose-6-phosphate

F2,6BP:

Fructose-2,6-bisphosphate

C J Ei or FCC:

Flux control coefficient

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

G3P:

Glyceraldehyde-3-phosphate

G6P:

Glucose-6-phosphate

GLUT:

Glucose transporter

HK:

Hexokinase

HPI:

Hexosephosphate isomerase

KC:

Krebs cycle

LDH:

Lactate dehydrogenase

OxPhos:

Oxidative phosphorylation

PEP:

Phosphoenolpyruvate

Pyr:

Pyruvate

PFK-1:

Phosphofructokinase type 1

PFKFB3:

Phosphofructokinase type 2 B3

6PG:

6-phosphogluconate

PGK:

Phosphoglycerate kinase

PGAM:

3-phosphoglycerate mutase

PYK:

Pyruvate kinase

TK:

Transketolase

TPI:

Triosephosphate isomerase.

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Acknowledgements

The present work was partially supported by the following grants from CONACyT-México: Nos. 180322 (AM-H); 107183 (SR-E); 80534 and 123636 (RM-S); and 83084 and 178638 (ES); and from the Instituto de Ciencia y Tecnología del Distrito Federal No. PICS08-5 (RM-S).

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Authors and Affiliations

  1. Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, México D.F., 14080, Mexico

    Alvaro Marín-Hernández, Sayra Y. López-Ramírez, Juan Carlos Gallardo-Pérez, Sara Rodríguez-Enríquez, Rafael Moreno-Sánchez & Emma Saavedra

  2. Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, México D.F., 14080, Mexico

    Sara Rodríguez-Enríquez

Authors
  1. Alvaro Marín-Hernández
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  2. Sayra Y. López-Ramírez
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  3. Juan Carlos Gallardo-Pérez
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  4. Sara Rodríguez-Enríquez
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  5. Rafael Moreno-Sánchez
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Corresponding authors

Correspondence to Rafael Moreno-Sánchez or Emma Saavedra .

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Editors and Affiliations

  1. School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA

    Miguel A. Aon

  2. Laboratory of Fundamental and Applied Bi, Inserm U1055 and University Joseph Fourier, Grenoble, Grenoble cedex 9, France

    Valdur Saks

  3. Laboratory of Fundamental and Applied Bi, Inserm U1055 and University Joseph Fourier, Grenoble, Grenoble cedex 9, France

    Uwe Schlattner

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Marín-Hernández, A., López-Ramírez, S.Y., Gallardo-Pérez, J.C., Rodríguez-Enríquez, S., Moreno-Sánchez, R., Saavedra, E. (2014). Systems Biology Approaches to Cancer Energy Metabolism. In: Aon, M., Saks, V., Schlattner, U. (eds) Systems Biology of Metabolic and Signaling Networks. Springer Series in Biophysics, vol 16. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38505-6_9

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