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

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1704145115 ◽

2017 ◽

Vol 114 (52) ◽

pp. 13732-13737 ◽

Cited By ~ 30

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.

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BAI1 acts as a tumor suppressor in lung cancer A549 cells by inducing metabolic reprogramming via the SCD1/HMGCR module

Carcinogenesis ◽

10.1093/carcin/bgaa036 ◽

2020 ◽

Author(s):

Lei Liu ◽

Li Chai ◽

Jingjing Ran ◽

Ying Yang ◽

Li Zhang

Keyword(s):

Lung Cancer ◽

Tumor Suppressor ◽

Colony Formation ◽

Warburg Effect ◽

Poor Prognosis ◽

A549 Cells ◽

Angiogenesis Inhibitor ◽

Metabolic Reprogramming ◽

The Warburg Effect

Abstract Brain-specific angiogenesis inhibitor 1 (BAI1) is an important tumor suppressor in multiple cancers. However, the mechanisms behind its anti-tumor activity, particularly the relationship between BAI1 and metabolic aberrant of a tumor, remained unveiled. This study aimed to investigate whether BAI1 could inhibit biological functions in lung cancer A549 cells and the critical regulating molecules that induce metabolic reprogramming. Immunohistochemistry staining was performed to analyze whether variations in the expression of BAI1 in tumor tissues contributes to poor prognosis of lung cancer. Overexpressed BAI1 (BAI1-OE-A549) and control (Vector-NC-A549) were generated by lentiviral transfection. Biological function assays (proliferation, apoptosis, colony formation, invasion and in vivo metastasis), as well as metabolic reprogramming (by the Warburg effect and the glycolytic rate), were performed in both groups. Our results indicated that lower levels of BAI1 contributed to poor prognosis of lung cancer patients. Furthermore, overexpressed of BAI1 dramatically inhibited proliferation, migration, invasion, colony formation and in vivo metastasis of A549 cells. The Warburg effect and the Seahorse assay revealed that BAI1-OE induced metabolism reprogramming by inhibiting the Warburg effect and glycolysis. Further exploration indicated that BAI1 induced metabolic reprogramming by upregulating stearoyl-CoA desaturase 1 (SCD1) and inhibited 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Our study revealed a novel mechanism through which BAI1 acted as tumor suppressor by inducing metabolic reprogramming via the SCD1 and HMGCR module.

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

Cancers ◽

10.3390/cancers13215557 ◽

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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Proton export drives the Warburg Effect

10.1101/2021.09.20.461019 ◽

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.

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Nicotinamide N‐methyltransferase decreases 5‐fluorouracil sensitivity in human esophageal squamous cell carcinoma through metabolic reprogramming and promoting the Warburg effect

Molecular Carcinogenesis ◽

10.1002/mc.23209 ◽

2020 ◽

Vol 59 (8) ◽

pp. 940-954

Author(s):

Yanyan Cui ◽

Dawei Yang ◽

Wenjie Wang ◽

Luyu Zhang ◽

Hongtao Liu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Warburg Effect ◽

Metabolic Reprogramming ◽

The Warburg Effect

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In vivo genetic dissection of tumor growth and the Warburg effect

eLife ◽

10.7554/elife.18126 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 44

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.

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

10.1101/2021.04.23.441208 ◽

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.

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The Warburg effect is necessary to promote glycosylation in the blastema during zebrafish tail regeneration

npj Regenerative Medicine ◽

10.1038/s41536-021-00163-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Jason W. Sinclair ◽

David R. Hoying ◽

Erica Bresciani ◽

Damian Dalle Nogare ◽

Carli D. Needle ◽

...

Keyword(s):

Glucose Metabolism ◽

Warburg Effect ◽

High Capacity ◽

Cell Types ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Tail Regeneration ◽

Hexosamine Biosynthetic Pathway ◽

Genetic Ablation ◽

The Warburg Effect

AbstractThroughout their lifetime, fish maintain a high capacity for regenerating complex tissues after injury. We utilized a larval tail regeneration assay in the zebrafish Danio rerio, which serves as an ideal model of appendage regeneration due to its easy manipulation, relatively simple mixture of cell types, and superior imaging properties. Regeneration of the embryonic zebrafish tail requires development of a blastema, a mass of dedifferentiated cells capable of replacing lost tissue, a crucial step in all known examples of appendage regeneration. Using this model, we show that tail amputation triggers an obligate metabolic shift to promote glucose metabolism during early regeneration similar to the Warburg effect observed in tumor forming cells. Inhibition of glucose metabolism did not affect the overall health of the embryo but completely blocked the tail from regenerating after amputation due to the failure to form a functional blastema. We performed a time series of single-cell RNA sequencing on regenerating tails with and without inhibition of glucose metabolism. We demonstrated that metabolic reprogramming is required for sustained TGF-β signaling and blocking glucose metabolism largely mimicked inhibition of TGF-β receptors, both resulting in an aberrant blastema. Finally, we showed using genetic ablation of three possible metabolic pathways for glucose, that metabolic reprogramming is required to provide glucose specifically to the hexosamine biosynthetic pathway while neither glycolysis nor the pentose phosphate pathway were necessary for regeneration.

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