Abstract
Background: Tumor cells often show altered metabolism which supports uncontrolled proliferation. A classic example is the Warburg effect: high glucose uptake and lactate production despite sufficient oxygen supply. Remarkably, tumor cells can transiently take up glucose even an order of magnitude faster when glucose is reintroduced after depletion. Regulation and significance of this high glucose uptake are investigated here. Methods: A new computational model was developed which reproduces two types of experimental data on Ehrlich ascites tumor cells: measurements by Otto Warburg of the average aerobic glycolytic rate during one hour (Warburg effect), and fast metabolic responses measured by others during the first minutes after reintroducing glucose. The model is subsequently extended with equations for glucose and O 2transport to predict the role of metabolism during fluctuations of blood flow in tumor tissue. Results: Model analysis reveals dynamic regulation of the head section of glycolysis where glucose uptake and phosphorylation occur. The head section is disinhibited slowly when concentrations of glycolytic intermediates fall, causing glucose uptake rate to considerably exceed that found by Warburg. The head section is partially inhibited in about a minute when sufficient glucose has been taken up. Simulations predict that tumors greedily take up glucose when blood flow resumes after periods of low flow. The cells then store glucose as fructose 1,6-bisphosphate and other glycolytic intermediates. During subsequent periods of low flow that cause O 2 and glucose depletion these stores are used for ATP production and biomass. Conclusions: The powerful glycolytic system in tumors not only synthesizes ATP at high steady rates, but can also store glycolytic intermediates to buffer temporary oxygen and nutrient shortages for up to 10 minutes. The head section of glycolysis in tumor cells, disinhibited during glucose shortages, becomes very efficient at stealing glucose from other cells, even at low glucose concentrations.
Highlights
Altered metabolism is an important characteristic of cancer cells and supports uncontrolled cell proliferation
Analysis of the new model in the present paper suggests that the head section of glycolysis can sequester glucose at very high capacity, but is downregulated quickly if glucose is taken up, falling to the still high steady-state levels of the Warburg effect
The small computational model developed in this study reproduces the three effects named after Warburg, Pasteur and Crabtree, respectively, which persist for hours as long as glucose is available; at the same time the model captures the kinetic behavior in the first minutes after glucose addition and it is consistent with biochemical knowledge
Summary
Altered metabolism is an important characteristic of cancer cells and supports uncontrolled cell proliferation. Warburg’s favorite experimental system to study this aerobic glycolysis were suspensions of mouse Ehrlich ascites tumor cells (EATC), which showed high aerobic glycolytic rates persisting for hours as long as glucose concentration 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. Methods: A new computational model was developed which reproduces two types of experimental data on Ehrlich ascites tumor cells: measurements by Otto Warburg of the average aerobic glycolytic rate during one hour (Warburg effect), and fast metabolic responses measured by others during the first minutes after reintroducing glucose. Conclusions: The powerful glycolytic system in tumors version 2
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