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.