scholarly journals The dynamic side of the Warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and O2 supply in tumor cells

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1177
Author(s):  
Johannes H.G.M. van Beek
Keyword(s):  
Blood Flow ◽  
Glucose Uptake ◽  
Tumor Cells ◽  
High Glucose ◽  
Warburg Effect ◽  
Low Flow ◽  
Glycolytic Intermediate ◽  
Head Section ◽  
Glycolytic Intermediates ◽  
The Warburg Effect

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 O2 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 O2 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.

scholarly journals The dynamic side of the Warburg effect: glycolytic intermediates as buffer for fluctuating glucose and O2 supply in tumor cells

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1177
Author(s):  
Johannes H.G.M. van Beek
Keyword(s):  
Glucose Uptake ◽  
Tumor Cells ◽  
High Glucose ◽  
Warburg Effect ◽  
Lactate Production ◽  
Tissue Blood Flow ◽  
Ascites Tumor ◽  
Head Section ◽  
Glycolytic Intermediates ◽  
The Warburg Effect

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 O2 and 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   O2 and 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.

scholarly journals Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

2016 ◽  
Vol 37 (8) ◽  
pp. 1013-1019 ◽  
Author(s):  
Xi-sha Chen ◽  
Lan-ya Li ◽  
Yi-di Guan ◽  
Jin-ming Yang ◽  
Yan Cheng
Keyword(s):  
Tumor Cells ◽  
Warburg Effect ◽  
Metabolic Profile ◽  
Therapeutic Targeting ◽  
The Warburg Effect

scholarly journals The Warburg effect: 80 years on

2016 ◽  
Vol 44 (5) ◽  
pp. 1499-1505 ◽  
Author(s):  
Michelle Potter ◽  
Emma Newport ◽  
Karl J. Morten
Keyword(s):  
Cancer Cells ◽  
High Glucose ◽  
Warburg Effect ◽  
Energy Requirement ◽  
Glucose Consumption ◽  
High Energy ◽  
Metabolic Reprogramming ◽  
Normal Cells ◽  
Cancer Types ◽  
The Warburg Effect

Influential research by Warburg and Cori in the 1920s ignited interest in how cancer cells' energy generation is different from that of normal cells. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria. It was therefore assumed that cancer cells were generating energy using glycolysis rather than mitochondrial oxidative phosphorylation, and that the mitochondria were dysfunctional. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types. However, different tumour populations have different bioenergetic alterations in order to meet their high energy requirement; the Warburg effect is not consistent across all cancer types. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer.

scholarly journals MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Nataly Shtraizent ◽  
Charles DeRossi ◽  
Shikha Nayar ◽  
Ravi Sachidanandam ◽  
Liora S Katz ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Mammalian Cells ◽  
Biosynthetic Pathway ◽  
Cellular Proliferation ◽  
Metabolic Enzyme ◽  
Chemical Methods ◽  
Hexosamine Biosynthetic Pathway ◽  
Glycolytic Intermediate ◽  
Functional Consequences ◽  
The Warburg Effect

Rapid cellular proliferation in early development and cancer depends on glucose metabolism to fuel macromolecule biosynthesis. Metabolic enzymes are presumed regulators of this glycolysis-driven metabolic program, known as the Warburg effect; however, few have been identified. We uncover a previously unappreciated role for Mannose phosphate isomerase (MPI) as a metabolic enzyme required to maintain Warburg metabolism in zebrafish embryos and in both primary and malignant mammalian cells. The functional consequences of MPI loss are striking: glycolysis is blocked and cells die. These phenotypes are caused by induction of p53 and accumulation of the glycolytic intermediate fructose 6-phosphate, leading to engagement of the hexosamine biosynthetic pathway (HBP), increased O-GlcNAcylation, and p53 stabilization. Inhibiting the HBP through genetic and chemical methods reverses p53 stabilization and rescues the Mpi-deficient phenotype. This work provides mechanistic evidence by which MPI loss induces p53, and identifies MPI as a novel regulator of p53 and Warburg metabolism.

scholarly journals MiR-21-5p inhibition attenuates Warburg effect and stemness maintenance in osteosarcoma cells via inactivation of Wnt/β-catenin signaling

2021 ◽  
Author(s):  
Yi Yu ◽  
Ziyan Wu ◽  
Zhong Zhou ◽  
Weiguo Zhang
Keyword(s):  
Lactic Acid ◽  
Cell Viability ◽  
Glucose Uptake ◽  
Warburg Effect ◽  
Acid Production ◽  
Lactic Acid Production ◽  
Osteosarcoma Cells ◽  
Atp Level ◽  
Potential Biomarker ◽  
The Warburg Effect

MicroRNA (miR)-21 has been found to be overexpressed in osteosarcoma (OS). The aim of the present study was to investigate the effect of miR-21-5p on the Warburg effect and stemness maintenance in OS cells and its potential molecular mechanism. Herein, miR-21-5p was overexpressed or inhibited in MG-63 cells via transfection with mimics or inhibitors. The effect of miR-21-5p on cell viability, apoptosis, Warburg effect and stemness maintenance were explored in OS cells. The results demonstrated that miR-21-5p inhibition suppressed MG-63 cell viability and enhanced their apoptosis. Additionally, miR-21-5p inhibition attenuated the stemness maintenance of MG-63 cells, as demonstrated by the reduced proportion of CD133-positive MG-63 cells, the decrease in tumorsphere formation capacity, and the downregulation of Sox2, Oct4, and Nanog proteins. Moreover, miR-21-5p inhibition suppressed the Warburg effect in MG-63 cells, as indicated by the decrease in glucose uptake, lactic acid production, and ATP level and the downregulation of proteins involved in the Warburg effect (GLUT1, LDHA, HK2, and PKM2). Furthermore, the results suggested that the effect of miR-21-5p suppression on stemness and the Warburg effect may be associated with the decreased activity of the Wnt/β-catenin pathway in OS cells. Our findings suggest a novel potential biomarker for OS therapy.

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