Abstract
Background:Tumor cells show the Warburg effect: high glucose uptake and lactate production despite sufficient oxygen supply. Otto Warburg found this effect in tissue slices and in suspensions of Ehrlich ascites tumor cells. Remarkably, these ascites tumor cells can transiently take up glucose an order of magnitude faster than the steady high rate measured by Warburg for hours.Methods:The purpose of the transiently very high glucose uptake is investigated here with a computational model of glycolysis, oxidative phosphorylation and ATP consumption which reproduces short kinetic experiments on the ascites tumor cells as well as the long-lasting Warburg, Crabtree and Pasteur effects. The model, extended with equations for glucose and O2 transport in tissue, is subsequently used to predict metabolism in tumor cells during fluctuations of tissue blood flow resulting in cycling hypoxia.Results:The model analysis suggests 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 are low. Based on these dynamic characteristics, simulations of tissue with fluctuating O2and glucose supply predict that tumor cells greedily take up glucose when this periodically becomes available, 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 O2and glucose shortages.Conclusions:The head section of glycolysis which phosphorylates glucose may be dynamically regulated and takes up glucose at rates exceeding the Warburg effect if glucose levels have been low for some time. The hypothesis is put forward here that dynamic regulation of the powerful glycolytic enzyme system in tumors is used to buffer oxygen and nutrient fluctuations in tissue.
Highlights
Cancer cells often show high lactate production despite sufficient oxygen supply, a phenomenon discovered by Otto Warburg1, and an example of widespread metabolic reprogramming in cancer2–4
The computational model consists of rate equations for the head and tail part of glycolysis, oxidative phosphorylation and lactate dehydrogenase which together determine the rate of change of the key metabolites in the model, captured in a system of ordinary differential equations
Two kinetic data sets for the first 3–5 min consist of responses to addition of 92 μM and 776 μM glucose to cells which had been grown in ascites fluid in mice and suspended in media without glucose
Summary
Cancer cells often show high lactate production despite sufficient oxygen supply, a phenomenon discovered by Otto Warburg, and an example of widespread metabolic reprogramming in cancer. Warburg’s favorite experimental system to study this effect were suspensions of mouse Ehrlich ascites tumor cells (EATC), which showed high aerobic glycolytic rates persisting for hours, at least when glucose concentrations remained high These EATC were later used by Warburg’s contemporaries to study the kinetics of metabolic responses in the first seconds and minutes after glucose addition to cells previously depleted of glucose, showing that glucose uptake is much higher in the first minute than averaged over one hour. Results: The model analysis suggests 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 are low 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, leaving very little for other cells. The hypothesis is put forward here that dynamic regulation of the powerful glycolytic enzyme system in tumors is used to buffer oxygen and nutrient fluctuations in tissue
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