title: Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism.
abstract: Applying basic biochemical principles, this review analyzes data that contrasts with the Warburg hypothesis that glycolysis is the exclusive ATP provider in cancer cells. Although disregarded for many years, there is increasing experimental evidence demonstrating that oxidative phosphorylation (OxPhos) makes a significant contribution to ATP supply in many cancer cell types and under a variety of conditions. Substrates oxidized by normal mitochondria such as amino acids and fatty acids are also avidly consumed by cancer cells. In this regard, the proposal that cancer cells metabolize glutamine for anabolic purposes without the need for a functional respiratory chain and OxPhos is analyzed considering thermodynamic and kinetic aspects for the reductive carboxylation of 2-oxoglutarate catalyzed by isocitrate dehydrogenase. In addition, metabolic control analysis (MCA) studies applied to energy metabolism of cancer cells are reevaluated. Regardless of the experimental/environmental conditions and the rate of lactate production, the flux-control of cancer glycolysis is robust in the sense that it involves the same steps: glucose transport, hexokinase, hexosephosphate isomerase and glycogen degradation, all at the beginning of the pathway; these steps together with phosphofructokinase 1 also control glycolysis in normal cells. The respiratory chain complexes exert significantly higher flux-control on OxPhos in cancer cells than in normal cells. Thus, determination of the contribution of each pathway to ATP supply and/or the flux-control distribution of both pathways in cancer cells is necessary in order to identify differences from normal cells which may lead to the design of rational alternative therapies that selectively target cancer energy metabolism.
authors: Instituto Nacional de Cardiología, Departamento de Bioquímica, Tlalpan, México D.F., Mexico. Electronic address: rafael.moreno@cardiologia.org.mx.
authors: Rafael
authors: R
authors: Moreno-Sánchez
authors: Instituto Nacional de Cardiología, Departamento de Bioquímica, Tlalpan, México D.F., Mexico.
authors: Alvaro
authors: A
authors: Marín-Hernández
authors: Instituto Nacional de Cardiología, Departamento de Bioquímica, Tlalpan, México D.F., Mexico.
authors: Emma
authors: E
authors: Saavedra
authors: Universidad Nacional Autónoma de México, Facultad de Medicina, Departamento de Bioquímica, México D.F., Mexico.
authors: Juan P
authors: JP
authors: Pardo
authors: School of Medical Sciences, Griffith University, Gold Coast Campus, Qld, Australia.
authors: Stephen J
authors: SJ
authors: Ralph
authors: Instituto Nacional de Cardiología, Departamento de Bioquímica, Tlalpan, México D.F., Mexico; Instituto Nacional de Cancerología, Laboratorio de Medicina Translacional, Tlalpan, México D.F., Mexico.
authors: Sara
authors: S
authors: Rodríguez-Enríquez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D004734:Energy Metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D010085:Oxidative Phosphorylation
chemical_list: D005973:Glutamine; D000255:Adenosine Triphosphate
keywords: Cancer glutamine metabolism; Isocitrate dehydrogenase; Oxidative phosphorylation; Warburg hypothesis