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 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 Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5557
Author(s):  
Alexandre Vallée ◽  
Yves Lecarpentier ◽  
Jean-Noël Vallée
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Warburg Effect ◽  
Target Genes ◽  
Glucose Transporter ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Pyruvate Dehydrogenase Kinase ◽  
The Warburg Effect

The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth.

scholarly journals Proton export drives the Warburg Effect

2021 ◽  
Author(s):  
Shonagh Russell ◽  
Liping Xu ◽  
Yoonseok Kam ◽  
Dominique Abrahams ◽  
Bryce Ordway ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Glycolytic Enzymes ◽  
Hek293 Cells ◽  
Driver Mutations ◽  
The Warburg Effect

Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the “Warburg Effect”. It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. To test this hypothesis, we stably transfected lowly-glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton exporting systems: either PMA1 (yeast H+-ATPase) or CAIX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. Therefore, cancer cells with increased H+ export increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards a Warburg phenotype.

The Warburg effect promoted the activation of the NLRP3 inflammasome induced by Ni-refining fumes in BEAS-2B cells

2020 ◽  
Vol 36 (8) ◽  
pp. 580-590
Author(s):  
Rui Wang ◽  
Sheng-Yuan Wang ◽  
Yue Wang ◽  
Rui Xin ◽  
Bing Xia ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Warburg Effect ◽  
Hypoxia Inducible Factor ◽  
Lactate Production ◽  
Control Group ◽  
Dependent Manner ◽  
Chain Reactions ◽  
Protein Levels ◽  
Polymerase Chain Reactions ◽  
The Warburg Effect

Nickel (Ni) is a known human carcinogen that has an adverse effect on various human organs in occupational workers during Ni refinement and smelting. In the present study, we used real-time polymerase chain reactions, Western blot analysis, and a lactate production assay to investigate whether an increase in the NLRP3 inflammasome induced by Ni-refining fumes was associated with the Warburg effect in BEAS-2B cells, a nonmalignant pulmonary epithelial line. Exposure to Ni-refining fumes suppressed cell proliferation and increased lactate production compared with those in an untreated control group in a dose- and time-dependent manner. Ni-refining fumes induced the Warburg effect, which was observed based on increases in the levels of hypoxia-inducible factor-1α, hexokinase 2, pyruvate kinase isozyme type M2, and lactate dehydrogenase A. In addition, Ni-refining fumes promoted increased expression of NLRP3 at both the gene and protein levels. Furthermore, inhibition of the Warburg effect by 2-Deoxy-d-glucose reversed the increased expression of NLRP3 induced by Ni-refining fumes. Collectively, our data demonstrated that the Warburg effect can promote the expression of the NLRP3 inflammasome induced by the Ni-refining fumes in BEAS-2B cells. This indicates a new phenomenon in which alterations in energy production in human cells induced by Ni-refining fumes regulate the inflammatory response.

scholarly journals Cell-Type Specific Metabolic Response of Cancer Cells to Curcumin

2020 ◽  
Vol 21 (5) ◽  
pp. 1661
Author(s):  
Anamarija Mojzeš ◽  
Marko Tomljanović ◽  
Lidija Milković ◽  
Renata Novak Kujundžić ◽  
Ana Čipak Gašparović ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Intracellular Localization ◽  
Lactate Production ◽  
Glucose Consumption ◽  
Cell Type ◽  
Cell Type Specific ◽  
The Warburg Effect

In order to support uncontrolled proliferation, cancer cells need to adapt to increased energetic and biosynthetic requirements. One such adjustment is aerobic glycolysis or the Warburg effect. It is characterized by increased glucose uptake and lactate production. Curcumin, a natural compound, has been shown to interact with multiple molecules and signaling pathways in cancer cells, including those relevant for cell metabolism. The effect of curcumin and its solvent, ethanol, was explored on four different cancer cell lines, in which the Warburg effect varied. Vital cellular parameters (proliferation, viability) were measured along with the glucose consumption and lactate production. The transcripts of pyruvate kinase 1 and 2 (PKM1, PKM2), serine hydroxymethyltransferase 2 (SHMT2) and phosphoglycerate dehydrogenase (PHGDH) were quantified with RT-qPCR. The amount and intracellular localization of PKM1, PKM2 and signal transducer and activator of transcription 3 (STAT3) proteins were analyzed by Western blot. The response to ethanol and curcumin seemed to be cell-type specific, with respect to all parameters analyzed. High sensitivity to curcumin was present in the cell lines originating from head and neck squamous cell carcinomas: FaDu, Detroit 562 and, especially, Cal27. Very low sensitivity was observed in the colon adenocarcinoma-originating HT-29 cell line, which retained, after exposure to curcumin, a higher levels of lactate production despite decreased glucose consumption. The effects of ethanol were significant.

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.

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