scholarly journals Evolved resistance to GAPDH inhibition results in loss of the Warburg Effect but retains a different state of glycolysis

2019 ◽  
Author(s):  
Maria V. Liberti ◽  
Annamarie E. Allen ◽  
Vijyendra Ramesh ◽  
Ziwei Dai ◽  
Katherine R. Singleton ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
Acid Metabolism ◽  
Aerobic Glycolysis ◽  
Specific Inhibitor ◽  
Central Carbon Metabolism ◽  
Glycolytic Enzyme ◽  
Altered State ◽  
The Warburg Effect

SUMMARYAerobic glycolysis or the Warburg Effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although ubiquitous, the biological role of the WE remains controversial and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, we evolved resistance to koningic acid (KA), a natural product shown to be a specific inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme during the WE. We find that KA-resistant cells lose the WE but conduct glycolysis and surprisingly remain dependent on glucose and central carbon metabolism. Consequentially this altered state of glycolysis leads to differential metabolic activity and requirements including emergent activities in and dependencies on fatty acid metabolism. Together, these findings reveal that, contrary to some recent reports, aerobic glycolysis is a functionally distinct entity from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.

scholarly journals Vacuolar H+-ATPase Subunit V0C Regulates Aerobic Glycolysis of Esophageal Cancer Cells via PKM2 Signaling

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1137 ◽  
Author(s):  
Sung Wook Son ◽  
Gia Cac Chau ◽  
Seong-Tae Kim ◽  
Sung Hee Um
Keyword(s):  
Esophageal Cancer ◽  
Glucose Metabolism ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Aerobic Glycolysis ◽  
Glycolytic Enzyme ◽  
Ph Homeostasis ◽  
Atpase Subunit ◽  
Esophageal Cancer Cells

The vacuolar H+-adenosine triphosphatase (ATPase) subunit V0C (ATP6V0C), a proton-conducting, pore-forming subunit of vacuolar ATPase, maintains pH homeostasis and induces organelle acidification. The intracellular and extracellular pH of cancer cells affects their growth; however, the role of ATP6V0C in highly invasive esophageal cancer cells (ECCs) remains unclear. In this study, we examined the role of ATP6V0C in glucose metabolism in ECCs. The ATP6V0C depletion attenuated ECC proliferation, invasion, and suppressed glucose metabolism, as indicated by reduced glucose uptake and decreased lactate and adenosine triphosphate (ATP) production in cells. Consistent with this, expression of glycolytic enzyme and the extracellular acidification rate (ECAR) were also decreased by ATP6V0C knockdown. Mechanistically, ATP6V0C interacted with pyruvate kinase isoform M2 (PKM2), a key regulator of glycolysis in ECCs. The ATP6V0C depletion reduced PKM2 phosphorylation at tyrosine residue 105 (Tyr105), leading to inhibition of nuclear translocation of PKM2. In addition, ATP6V0C was recruited at hypoxia response element (HRE) sites in the lactate dehydrogenase A (LDHA) gene for glycolysis. Thus, our data suggest that ATP6V0C enhances aerobic glycolysis and motility in ECCs.

scholarly journals Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

2021 ◽  
Vol 22 (12) ◽  
pp. 6434
Author(s):  
Aldona Kasprzak
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Glucose Metabolism ◽  
Warburg Effect ◽  
Mapk Signaling ◽  
Colorectal Carcinogenesis ◽  
Insulin Like Growth Factor ◽  
Aberrant Expression ◽  
The Warburg Effect

Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.

scholarly journals Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jing Cui ◽  
Yao Guo ◽  
Heshui Wu ◽  
Jiongxin Xiong ◽  
Tao Peng
Keyword(s):  
Pancreatic Cancer ◽  
Glucose Metabolism ◽  
Cell Viability ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Mtor Signaling ◽  
Glucose Transporter 1 ◽  
Pancreatic Cancer Cells ◽  
The Warburg Effect

Abstract Background Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. Methods The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEMsen) and GEM-resistant (GEMres) pancreatic cancer cells. Results We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEMsen and GEMres cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEMres cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEMres cells than that in GEMsen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEMres tumors, Evr significantly decreased the volume of GEMres tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. Conclusions Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.

scholarly journals Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism

2018 ◽  
Vol 293 (41) ◽  
pp. 15947-15961 ◽  
Author(s):  
Maša Ždralević ◽  
Almut Brand ◽  
Lorenza Di Ianni ◽  
Katja Dettmer ◽  
Jörg Reinders ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Warburg Effect ◽  
Specific Inhibitor ◽  
Glucose Consumption ◽  
Glycolytic Enzyme ◽  
Double Knockout ◽  
Genetic Block ◽  
The Warburg Effect

Increased glucose consumption distinguishes cancer cells from normal cells and is known as the “Warburg effect” because of increased glycolysis. Lactate dehydrogenase A (LDHA) is a key glycolytic enzyme, a hallmark of aggressive cancers, and believed to be the major enzyme responsible for pyruvate-to-lactate conversion. To elucidate its role in tumor growth, we disrupted both the LDHA and LDHB genes in two cancer cell lines (human colon adenocarcinoma and murine melanoma cells). Surprisingly, neither LDHA nor LDHB knockout strongly reduced lactate secretion. In contrast, double knockout (LDHA/B-DKO) fully suppressed LDH activity and lactate secretion. Furthermore, under normoxia, LDHA/B-DKO cells survived the genetic block by shifting their metabolism to oxidative phosphorylation (OXPHOS), entailing a 2-fold reduction in proliferation rates in vitro and in vivo compared with their WT counterparts. Under hypoxia (1% oxygen), however, LDHA/B suppression completely abolished in vitro growth, consistent with the reliance on OXPHOS. Interestingly, activation of the respiratory capacity operated by the LDHA/B-DKO genetic block as well as the resilient growth were not consequences of long-term adaptation. They could be reproduced pharmacologically by treating WT cells with an LDHA/B-specific inhibitor (GNE-140). These findings demonstrate that the Warburg effect is not only based on high LDHA expression, as both LDHA and LDHB need to be deleted to suppress fermentative glycolysis. Finally, we demonstrate that the Warburg effect is dispensable even in aggressive tumors and that the metabolic shift to OXPHOS caused by LDHA/B genetic disruptions is responsible for the tumors' escape and growth.

scholarly journals Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect

2011 ◽  
Vol 108 (39) ◽  
pp. 16259-16264 ◽  
Author(s):  
C. Zhang ◽  
M. Lin ◽  
R. Wu ◽  
X. Wang ◽  
B. Yang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
Target Gene ◽  
P53 Target Gene ◽  
The Warburg Effect

scholarly journals The Role of Glucose Metabolism and Glucose-Associated Signalling in Cancer

2007 ◽  
Vol 1 ◽  
pp. 1177391X0700100 ◽  
Author(s):  
Rainer Wittig ◽  
Johannes F. Coy
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
Genetic Manipulation ◽  
Aerobic Glycolysis ◽  
Nobel Laureate ◽  
Pentose Phosphate ◽  
Pharmacological Intervention ◽  
Otto Warburg ◽  
The Warburg Effect ◽  
Glycolytic Phenotype

Aggressive carcinomas ferment glucose to lactate even in the presence of oxygen. This particular metabolism, termed aerobic glycolysis, the glycolytic phenotype, or the Warburg effect, was discovered by Nobel laureate Otto Warburg in the 1920s. Since these times, controversial discussions about the relevance of the fermentation of glucose by tumours took place; however, a majority of cancer researchers considered the Warburg effect as a non-causative epiphenomenon. Recent research demonstrated, that several common oncogenic events favour the expression of the glycolytic phenotype. Moreover, a suppression of the phenotypic features by either substrate limitation, pharmacological intervention, or genetic manipulation was found to mediate potent tumour-suppressive effects. The discovery of the transketolase-like 1 (TKTL1) enzyme in aggressive cancers may deliver a missing link in the interpretation of the Warburg effect. TKTL1-activity could be the basis for a rapid fermentation of glucose in aggressive carcinoma cells via the pentose phosphate pathway, which leads to matrix acidification, invasive growth, and ultimately metastasis. TKTL1 expression in certain non-cancerous tissues correlates with aerobic formation of lactate and rapid fermentation of glucose, which may be required for the prevention of advanced glycation end products and the suppression of reactive oxygen species. There is evidence, that the activity of this enzyme and the Warburg effect can be both protective or destructive for the organism. These results place glucose metabolism to the centre of pathogenesis of several civilisation related diseases and raise concerns about the high glycaemic index of various food components commonly consumed in western diets.

scholarly journals Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme

2011 ◽  
Vol 208 (2) ◽  
pp. 313-326 ◽  
Author(s):  
Amparo Wolf ◽  
Sameer Agnihotri ◽  
Johann Micallef ◽  
Joydeep Mukherjee ◽  
Nesrin Sabha ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Glycolytic Enzyme ◽  
Low Grade ◽  
Normal Brain ◽  
Hexokinase 2 ◽  
Human Glioblastoma ◽  
Human Glioblastoma Multiforme ◽  
The Warburg Effect

Proliferating embryonic and cancer cells preferentially use aerobic glycolysis to support growth, a metabolic alteration commonly referred to as the “Warburg effect.” Here, we show that the glycolytic enzyme hexokinase 2 (HK2) is crucial for the Warburg effect in human glioblastoma multiforme (GBM), the most common malignant brain tumor. In contrast to normal brain and low-grade gliomas, which express predominantly HK1, GBMs show increased HK2 expression. HK2 expression correlates with worse overall survival of GBM patients. Depletion of HK2, but neither HK1 nor pyruvate kinase M2, in GBM cells restored oxidative glucose metabolism and increased sensitivity to cell death inducers such as radiation and temozolomide. Intracranial xenografts of HK2-depleted GBM cells showed decreased proliferation and angiogenesis, but increased invasion, as well as diminished expression of hypoxia inducible factor 1α and vascular endothelial growth factor. In contrast, exogenous HK2 expression in GBM cells led to increased proliferation, therapeutic resistance, and intracranial growth. Growth was dependent on both glucose phosphorylation and mitochondrial translocation mediated by AKT signaling, which is often aberrantly activated in GBMs. Collectively, these findings suggest that therapeutic strategies to modulate the Warburg effect, such as targeting of HK2, may interfere with growth and therapeutic sensitivity of some GBMs.

scholarly journals Influence of SNF1 complex on growth, glucose metabolism and mitochondrial respiration ofSaccharomyces cerevisiae

2018 ◽  
Author(s):  
Cecilia Martinez-Ortiz ◽  
Andres Carrillo-Garmendia ◽  
Blanca Flor Correa-Romero ◽  
Melina Canizal-García ◽  
Juan Carlos González-Hernández ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Mitochondrial Respiration ◽  
Warburg Effect ◽  
Gene Deletion ◽  
Glycolytic Flux ◽  
Crabtree Effect ◽  
Main Pathway ◽  
Molecular Etiology ◽  
The Warburg Effect

AbstractThe switch of mitochondrial respiration to fermentation as the main pathway to produce ATP through the increase of glycolytic flux is known as the Crabtree effect. The elucidation of the molecular mechanism of the Crabtree effect may have important applications in ethanol production and lay the groundwork for the Warburg effect, which is essential in the molecular etiology of cancer. A key piece in this mechanism could be Snf1p, which is a protein that participates in the nutritional response that includes glucose metabolism. Thus, this work aimed to recognize the role of the SNF1 complex on the glycolytic flux and mitochondrial respiration, to gain insights about its relationship with the Crabtree effect. Herein, we found that inSaccharomyces cerevisiaecells grown at 1% glucose, mutation ofSNF1gene decreased glycolytic flux, increased NAD(P)H, enhancedHXK2gene transcription, and decreased mitochondrial respiration. Meanwhile, the same mutation increased the mitochondrial respiration of cells grown at 10% glucose. Moreover,SNF4gene deletion increased respiration and growth at 1% of glucose. In the case of theGAL83gene, we did not detect any change in mitochondrial respiration or growth. Altogether, these findings indicate thatSNF1is vital to switch from mitochondrial respiration to fermentation.

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.

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