Systems Biology Approaches to Cancer Energy Metabolism - Systems Biology of Metabolic and Signaling Networks - page 207

Chapter 9
Systems Biology Approaches to Cancer
Energy Metabolism

Alvaro Mar ´ n-Hern ´ ndez, Sayra Y. L ´ pez-Ram ´ rez,
Juan Carlos Gallardo-P ´ rez, Sara Rodr ´ guez-Enr ´ quez,
Rafael Moreno-S´nchez, and Emma Saavedra

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. Mito-
chondrial metabolism is also active and essential for cancer cells. Therefore, a
cancer energy metabolism model, including glycolysis and oxidative

A. Mar ´ n-Hern ´ ndez • S.Y. L ´ pez-Ram ´ rez • J.C. Gallardo-P ´ rez • R. Moreno-S ´ nchez ( * )•
E. Saavedra ( * )
Departamento de Bioqu´mica, Instituto Nacional de Cardiolog´a Ignacio Ch´vez, Juan Badiano
No. 1, Col. Secci´n XVI, Tlalpan, M´xico D.F. 14080, Mexico
e-mail: [e-mail] ; [e-mail]
S. Rodr´guez-Enr´quez
Departamento de Bioqu´mica, Instituto Nacional de Cardiolog´a Ignacio Ch´vez, Juan Badiano
No. 1, Col. Secci´n XVI, Tlalpan, M´xico D.F. 14080, Mexico
Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerolog´a, M´xico D.F.
14080, Mexico