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 Aerobic glycolysis is important for zebrafish larval wound closure and tail regeneration

2021 ◽  
Author(s):  
Claire A. Scott ◽  
Tom J. Carney ◽  
Enrique Amaya
Keyword(s):  
Warburg Effect ◽  
Wound Closure ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Significant Advance ◽  
Tail Regeneration ◽  
Lactate Levels ◽  
The Warburg Effect

ABSTRACTThe underlying mechanisms of appendage regeneration remain largely unknown, and uncovering these mechanisms in capable organisms have far-reaching implications for potential treatments in humans. Recent studies implicate a requirement for metabolic reprogramming reminiscent of the Warburg effect during successful appendage and organ regeneration. Changes are thus predicted to be highly dynamic, methods permitting direct visualization of metabolites at the tissue and organismal level, in real time, would offer a significant advance in defining the influence of metabolism on regeneration and healing. We sought to examine whether glycolytic activity was altered during larval fin regeneration, utilising the genetically encoded biosensor, Laconic, enabling the spatiotemporal assessment of lactate levels in living zebrafish. We present evidence for a rapid increase in lactate levels within minutes following injury, with a role of aerobic glycolysis in actomyosin contraction and wound closure. We also find a second wave of lactate production, associated with overall larval tail regeneration. Chemical inhibition of glycolysis attenuates both contraction of the wound and regrowth of tissue following tail amputation, suggesting aerobic glycolysis is necessary at two distinct stages of regeneration.SUMMARY STATEMENTBy combining a genetically encoded lactate FRET sensor with chemical inhibitors, we demonstrate a critical role for the Warburg effect and metabolic reprogramming during zebrafish wound closure and tail regeneration.

scholarly journals Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3018
Author(s):  
Marek Samec ◽  
Alena Liskova ◽  
Lenka Koklesova ◽  
Kevin Zhai ◽  
Elizabeth Varghese ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Glucose Transporter ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Lactate Production ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Effective Prevention ◽  
Anti Cancer ◽  
Glucose 6 Phosphate Dehydrogenase

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

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.

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 O-GlcNAcylation destabilizes the active tetrameric PKM2 to promote the Warburg effect

2017 ◽  
Vol 114 (52) ◽  
pp. 13732-13737 ◽  
Author(s):  
Yang Wang ◽  
Jia Liu ◽  
Xin Jin ◽  
Dapeng Zhang ◽  
Dongxue Li ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Nuclear Translocation ◽  
Lactate Production ◽  
Human Tumor ◽  
Glucose Consumption ◽  
Metabolic Reprogramming ◽  
Proliferating Cells ◽  
The Warburg Effect

The Warburg effect, characterized by increased glucose uptake and lactate production, is a well-known universal across cancer cells and other proliferating cells. PKM2, a splice isoform of the pyruvate kinase (PK) specifically expressed in these cells, serves as a major regulator of this metabolic reprogramming with an adjustable activity subjected to numerous allosteric effectors and posttranslational modifications. Here, we have identified a posttranslational modification on PKM2, O-GlcNAcylation, which specifically targets Thr405 and Ser406, residues of the region encoded by the alternatively spliced exon 10 in cancer cells. We show that PKM2 O-GlcNAcylation is up-regulated in various types of human tumor cells and patient tumor tissues. The modification destabilized the active tetrameric PKM2, reduced PK activity, and led to nuclear translocation of PKM2. We also observed that the modification was associated with an increased glucose consumption and lactate production and enhanced level of lipid and DNA synthesis, indicating that O-GlcNAcylation promotes the Warburg effect. In vivo experiments showed that blocking PKM2 O-GlcNAcylation attenuated tumor growth. Thus, we demonstrate that O-GlcNAcylation is a regulatory mechanism for PKM2 in cancer cells and serves as a bridge between PKM2 and metabolic reprogramming typical of the Warburg effect.

scholarly journals In vivo genetic dissection of tumor growth and the Warburg effect

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Cheng-Wei Wang ◽  
Arunima Purkayastha ◽  
Kevin T Jones ◽  
Shivani K Thaker ◽  
Utpal Banerjee
Keyword(s):  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Feedback Signal ◽  
Vegf Receptor ◽  
Genetic Dissection ◽  
Oncogenic Pathways ◽  
Genes Encoding ◽  
The Warburg Effect

A well-characterized metabolic landmark for aggressive cancers is the reprogramming from oxidative phosphorylation to aerobic glycolysis, referred to as the Warburg effect. Models mimicking this process are often incomplete due to genetic complexities of tumors and cell lines containing unmapped collaborating mutations. In order to establish a system where individual components of oncogenic signals and metabolic pathways can be readily elucidated, we induced a glycolytic tumor in the Drosophila wing imaginal disc by activating the oncogene PDGF/VEGF-receptor (Pvr). This causes activation of multiple oncogenic pathways including Ras, PI3K/Akt, Raf/ERK, Src and JNK. Together this network of genes stabilizes Hifα (Sima) that in turn, transcriptionally up-regulates many genes encoding glycolytic enzymes. Collectively, this network of genes also causes inhibition of pyruvate dehydrogenase (PDH) activity resulting in diminished ox-phos levels. The high ROS produced during this process functions as a feedback signal to consolidate this metabolic reprogramming.

scholarly journals Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2743
Author(s):  
Caterina Miro ◽  
Annarita Nappi ◽  
Annunziata Gaetana Cicatiello ◽  
Emery Di Cicco ◽  
Serena Sagliocchi ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Squamous Cell ◽  
Warburg Effect ◽  
Lactate Production ◽  
Metabolic Stress ◽  
Cell Types ◽  
Metabolic Reprogramming ◽  
Glycolytic Flux ◽  
The Warburg Effect

Cancer angiogenesis is required to support energetic demand and metabolic stress, particularly during conditions of hypoxia. Coupled to neo-vasculogenesis, cancer cells rewire metabolic programs to sustain growth, survival and long-term maintenance. Thyroid hormone (TH) signaling regulates growth and differentiation in a variety of cell types and tissues, thus modulating hyper proliferative processes such as cancer. Herein, we report that TH coordinates a global program of metabolic reprogramming and induces angiogenesis through up-regulation of the VEGF-A gene, which results in the enhanced proliferation of tumor endothelial cells. In vivo conditional depletion of the TH activating enzyme in a mouse model of cutaneous squamous cell carcinoma (SCC) reduces the concentration of TH in the tumoral cells and results in impaired VEGF-A production and attenuated angiogenesis. In addition, we found that TH induces the expression of the glycolytic genes and fosters lactate production, which are key traits of the Warburg effect. Taken together, our results reveal a TH–VEGF-A–HIF1α regulatory axis leading to enhanced angiogenesis and glycolytic flux, which may represent a target for SCC therapy.

Non-dietary Fructose Metabolism Contributes to the Warburg effect in Cancers

2020 ◽  
Author(s):  
Bing Han ◽  
Lu Wang ◽  
Meilin Wei ◽  
Cynthia Rajani ◽  
Runming Wei ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Glucose Transporter ◽  
Self Control ◽  
Metabolic Reprogramming ◽  
Atp Production ◽  
Fructose Metabolism ◽  
Energy Needs ◽  
Dietary Fructose ◽  
The Warburg Effect

AbstractFructose metabolism is increasingly recognized as a preferred energy source for cancer cell proliferation. However, dietary fructose rarely enters the bloodstream. Therefore, it remains unclear how cancer cells acquire a sufficient amount of fructose to supplement their energy needs. Here we report that the cancer cells can convert glucose into fructose through intra- and extracellular polyol pathways. The fructose metabolism bypasses normal aerobic respiration’s self-control to supply excessive metabolites to glycolysis and causes the Warburg effect. Inhibition of fructose production drastically suppressed glycolysis and ATP production in cancers. Furthermore, we determined that a glucose transporter, SLC2A8/GLUT8, exports intracellular fructose to other cells in the tumor microenvironment. Taken together, our study identified overlooked fructose resources for cancer cells as an essential part of their metabolic reprogramming and caused the Warburg effect.Statement of SignificanceOur findings in this study suggest that the Warburg effect is actually achieved by means of fructose metabolism, instead of glucose metabolism alone. Fructose metabolism results in accelerated glycolysis and an increased amount of ATP and key intermediates for anabolic metabolism.

Aerobic Glycolysis: A Possible Target for Treating Multiple Myeloma (MM) with High Serum LDH Levels

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1799-1799 ◽  
Author(s):  
Shiho Fujiwara ◽  
Yawara Kawano ◽  
Hiromichi Yuki ◽  
Yutaka Okuno ◽  
Kisato Nosaka ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Lines ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Glucose Consumption ◽  
High Serum ◽  
Expression Levels ◽  
Key Enzyme ◽  
The Warburg Effect

Abstract Abstract 1799 Introduction: A number of studies have shown that the high level of serum lactate dehydrogenase (LDH) serves as an indicator for poor prognosis in multiple myeloma (MM). LDH is a key enzyme for glycolysis converting pyruvate to lactate, which is eventually utilized as an energy source particularly in tumor cells. It has been reported that cancer cells utilize this glycolysis pathway even in the presence of adequate oxygen to provide cancer cells with energy, called the Warburg effect (aerobic glycolysis). Myc is known to regulate LDH and pyruvate dehydrogenase kinase 1 (PDK1), which are master regulators of glycolysis (Figure 1). Although myc is a well known gene expressed in MM cells, there has been no report analyzing its association with the glycolysis-regulating genetic system, which is located downstream to the myc gene, in MM cells. In the present study, we examined if the glycolysis system is directly or indirectly associated with the survival of MM cells. Methods: MM cells were purified from primary bone marrow samples from 54 patients using CD138-magnetic beads. Written informed consent was obtained from all cases. Seven MM cell lines, RPMI8226, U266, KMS12BM, KMS12PE, KHM11, KMM1 and KMS11, were employed. Five genes associated with glycolysis, i.e., c-MYC, GLUT1 (glucose transporter 1), LDHA (LDH-encoding gene), hypoxia induced factor-1 alpha (HIF1a) and PDK1, were examined using real time PCR analysis. Glucose consumption and lactate production in culture supernatants of MM cell lines were analyzed. Oxamate, a competitive inhibitor of LDHA, was utilized to quantify cytotoxic effects on MM cells. Cytotoxicity was evaluated with AnnexinV/PI staining. Results: Heterogeneous expression of LDHA gene was observed (Figure 2A). High LDHA mRNA expression levels significantly correlated with poor survival (Figure 2B, p<0.01). A significant correlation between serum LDH levels and the mRNA expression levels of LDHA, was also found (p<0.01). Moreover, LDHA mRNA expression was significantly higher in MM cells than in plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS) (p<0.01). LDHA expression levels correlated with the expression levels of (i) c-MYC (p<0.0001) (ii) PDK1 (p<0.0023), a key enzyme regulating the Warburg effect, and (iii) GLUT1 (p<0.0003), while it did not correlate with HIF1a expression. It was also found that the greater glucose consumption, the greater lactate production as well as LDH activity in MM cell lines with higher LDHA mRNA expression. Finally, we found that an LDH-inhibitor, oxamate, activated caspase-3 (Figure 3) and induced apoptosis in MM cell lines as well as primary MM cells. Conclusion: Our results suggest that aerobic glycolysis (the Warburg effect) is up-regulated in MM cells of patients with high serum LDH levels and that the aberrant expression of LDHA, PDK1 and GLUT1 is critical for the survival of MM cells with high serum LDH levels. Thus, aerobic glycolysis itself could serve as a novel therapeutic target in MM patients. Since MM with high serum LDH is with poor prognosis even after the advent of new agents, the present data might have a clinical relevance and might open a new avenue to develop novel therapeutic modalities for treating MM with high serum LDH levels. Disclosures: No relevant conflicts of interest to declare.

Vasculogenesis and angiogenesis initiation under normoxic conditions through Wnt/β-catenin pathway in gliomas

2017 ◽  
Vol 29 (1) ◽  
pp. 71-91 ◽  
Author(s):  
Alexandre Vallée ◽  
Rémy Guillevin ◽  
Jean-Noël Vallée
Keyword(s):  
Growth Factor ◽  
Cyclin D1 ◽  
Target Genes ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Translation Initiation Factor ◽  
Pyruvate Dehydrogenase Kinase ◽  
Initiation Factor ◽  
Prolyl Hydroxylation ◽  
Vasculogenesis And Angiogenesis

AbstractThe canonical Wnt/β-catenin pathway is up-regulated in gliomas and involved in proliferation, invasion, apoptosis, vasculogenesis and angiogenesis. Nuclear β-catenin accumulation correlates with malignancy. Hypoxia activates hypoxia-inducible factor (HIF)-1α by inhibiting HIF-1α prolyl hydroxylation, which promotes glycolytic energy metabolism, vasculogenesis and angiogenesis, whereas HIF-1α is degraded by the HIF prolyl hydroxylase under normoxic conditions. We focus this review on the links between the activated Wnt/β-catenin pathway and the mechanisms underlying vasculogenesis and angiogenesis through HIF-1α under normoxic conditions in gliomas. Wnt-induced epidermal growth factor receptor/phosphatidylinositol 3-kinase (PI3K)/Akt signaling, Wnt-induced signal transducers and activators of transcription 3 (STAT3) signaling, and Wnt/β-catenin target gene transduction (c-Myc) can activate HIF-1α in a hypoxia-independent manner. The PI3K/Akt/mammalian target of rapamycin pathway activates HIF-1α through eukaryotic translation initiation factor 4E-binding protein 1 and STAT3. The β-catenin/T-cell factor 4 complex directly binds to STAT3 and activates HIF-1α, which up-regulates the Wnt/β-catenin target genes cyclin D1 and c-Myc in a positive feedback loop. Phosphorylated STAT3 by interleukin-6 or leukemia inhibitory factor activates HIF-1α even under normoxic conditions. The activation of the Wnt/β-catenin pathway induces, via the Wnt target genes c-Myc and cyclin D1 or via HIF-1α, gene transactivation encoding aerobic glycolysis enzymes, such as glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production, as the primary alternative of ATP, at all oxygen levels, even in normoxic conditions. Lactate released by glioma cells via the monocarboxylate lactate transporter-1 up-regulated by HIF-1α and lactate anion activates HIF-1α in normoxic endothelial cells by inhibiting HIF-1α prolyl hydroxylation and preventing HIF labeling by the von Hippel-Lindau protein. Increased lactate with acid environment and HIF-1α overexpression induce the vascular endothelial growth factor (VEGF) pathway of vasculogenesis and angiogenesis under normoxic conditions. Hypoxia and acidic pH have no synergistic effect on VEGF transcription.

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