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The dynamic side of the Warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and O (2) supply in tumor cells

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 fa...

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Autor principal: van Beek, Johannes H.G.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: F1000 Research Limited 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352925/
https://www.ncbi.nlm.nih.gov/pubmed/30755789
http://dx.doi.org/10.12688/f1000research.15635.2
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author van Beek, Johannes H.G.M.
author_facet van Beek, Johannes H.G.M.
author_sort van Beek, Johannes H.G.M.
collection PubMed
description 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 (2) transport 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.
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spelling pubmed-63529252019-02-11 The dynamic side of the Warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and O (2) supply in tumor cells van Beek, Johannes H.G.M. F1000Res Research Article 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 (2) transport 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. F1000 Research Limited 2018-12-28 /pmc/articles/PMC6352925/ /pubmed/30755789 http://dx.doi.org/10.12688/f1000research.15635.2 Text en Copyright: © 2018 van Beek JHGM http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
van Beek, Johannes H.G.M.
The dynamic side of the Warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and O (2) supply in tumor cells
title The dynamic side of the Warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and O (2) supply in tumor cells
title_full The dynamic side of the Warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and O (2) supply in tumor cells
title_fullStr The dynamic side of the Warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and O (2) supply in tumor cells
title_full_unstemmed The dynamic side of the Warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and O (2) supply in tumor cells
title_short The dynamic side of the Warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and O (2) supply in tumor cells
title_sort dynamic side of the warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and o (2) supply in tumor cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352925/
https://www.ncbi.nlm.nih.gov/pubmed/30755789
http://dx.doi.org/10.12688/f1000research.15635.2
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