Dynamic Side of the Warburg Effect: Glycolytic Intermediate Storage in Tumor Cells to Buffer Fluctuating Glucose and O2 Supply

Tumor cells show the Warburg effect: high glucose uptake and lactate production despite sufficient oxygen supply. A multi-scale computational model of tumor cell metabolism, intracellular metabolite storage and transport in tissue by blood flow and diffusion is developed here. This model is used to investigate the dynamic behavior of the metabolic system underlying the Warburg glycolytic phenotype. Remarkably, experiments have shown that the ascites tumor cells studied by Otto Warburg can transiently take up glucose an order of magnitude faster than the already high glycolytic rate that he measured for hours. This transiently very high glucose uptake is investigated here with a computational model that reproduces kinetic experiments on these ascites tumor cells. Model analysis of the data shows that the head section of the glycolytic chain in the tumor cells is partially inhibited in about a minute when substantial amounts of glucose have been taken up intracellularly. This head section of the glycolytic chain is subsequently disinhibited slowly when concentrations of glycolytic intermediates fall to low levels again. Based on these dynamic characteristics, simulations of tissue with fluctuating O₂ and glucose supply predict that tumor cells greedily take up glucose when this periodically becomes available at low concentrations, leaving very little for other cells. The glucose is stored as fructose 1,6-bisphosphate and other glycolytic intermediates, which are used for ATP production during O₂ and glucose shortages that last several minutes. This dynamic energy buffer capacity may have selective advantages for tumor cells experiencing cycling hypoxia and nutrient shortages, which are often found in cancer tissue. The hypothesis is put forward here that dynamic regulation of the powerful glycolytic enzyme system in tumor cells is used to buffer oxygen and nutrient fluctuations in tissue. The stored glycolytic intermediates can support the ATP requirements of the tumor cells for 2-10 minutes.