Genome-Scale Metabolic Modeling Elucidates the Role of Proliferative Adaptation in Causing the Warburg Effect

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.

Author Summary

Cancer cells, as opposed to normal cells, produce a substantial amount of energy inefficiently via aerobic glycolysis, even in the presence of sufficient oxygen to support mitochondrial respiration. Despite the fact that this phenomenon, called the Warburg effect, has already been discovered back in 1924, its causes remain poorly understood. Here we utilize a genome-scale human metabolic network model and show that by accounting for cellular capacity for metabolic enzymes, the Warburg effect is a direct consequence of cancer cells' adaptation to fast 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.