Abstract
The Warburg effect - a classical hallmark of cancer metabolism - is a counter-intuitive phenomenon in which rapidly proliferating cancer cells resort to inefficient ATP production via glycolysis leading to lactate secretion, instead of relying primarily on more efficient energy production through mitochondrial oxidative phosphorylation, as most normal cells do. The causes for the Warburg effect have remained a subject of considerable controversy since its discovery over 80 years ago, with several competing hypotheses. Here, utilizing a genome-scale human metabolic network model accounting for stoichiometric and enzyme solvent capacity considerations, we show that the Warburg effect is a direct consequence of the metabolic adaptation of cancer cells to increase biomass production rate. The analysis is shown to accurately capture a three phase metabolic behavior that is observed experimentally during oncogenic progression, as well as a prominent characteristic of cancer cells involving their preference for glutamine uptake over other amino acids.
Highlights
The Warburg effect, a phenomenon discovered by Otto Warburg in 1924, reflects a shift to an inefficient metabolism in cancer cells, in which an increase in the inefficient production of adenosine 59-triphosphate (ATP) via glycolysis leads to the secretion of non-oxidized carbons in the form of lactate, even in the presence of oxygen [1,2]
Production yields of the different pathways that catabolize carbon sources may cause the Warburg effect: the high-yield oxidative phosphorylation pathway has high enzyme costs, leading to a sub-optimal ATP production strategy, as it has lower production rates than glycolysis [16]. (vi) Metabolic adaptation to fast proliferation - it was argued that as opposed to metabolism in differentiated cells that is geared towards efficient ATP production, the aerobic glycolysis observed in cancer cells is adapted to facilitate biomass accumulation and high proliferation
We demonstrate that our model accurately captures several metabolic phenotypes observed experimentally during cancer development, as well as the preference of cancer cells to glutamine uptake over other amino acids
Summary
The Warburg effect, a phenomenon discovered by Otto Warburg in 1924, reflects a shift to an inefficient metabolism in cancer cells, in which an increase in the inefficient production of adenosine 59-triphosphate (ATP) via glycolysis leads to the secretion of non-oxidized carbons in the form of lactate, even in the presence of oxygen (termed aerobic glycolysis) [1,2]. The study of Vander Heiden et al manually computed the metabolic requirements for producing one essential biomass precursor, palmitate (a major constituent of cellular membranes) considering the stoichiometry of a few central metabolic pathways They found that aerobic glycolysis enables maximal palmitate production yield due to specific reducing power requirements. In another recent study, Vazquez et al employed a schematic model of ATP production in human cells (considering two lumped reactions representing aerobic glycolysis and oxidative phosphorylation), elegantly showing that a switch to aerobic glycolysis should result from cellular maximization of ATP production [18]. Their schematic model accounts for the stoichiometry of glycolysis and oxidative phosphyrylation and
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