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

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.

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Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer ◽

10.1016/j.bbcan.2018.06.005 ◽

2018 ◽

Vol 1870 (1) ◽

pp. 51-66 ◽

Cited By ~ 44

Author(s):

Linchong Sun ◽

Caixia Suo ◽

Shi-ting Li ◽

Huafeng Zhang ◽

Ping Gao

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Metabolic Reprogramming ◽

The Warburg Effect

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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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The Warburg effect: 80 years on

Biochemical Society Transactions ◽

10.1042/bst20160094 ◽

2016 ◽

Vol 44 (5) ◽

pp. 1499-1505 ◽

Cited By ~ 155

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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Retraction: Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells

Carcinogenesis ◽

10.1093/carcin/bgz056 ◽

2019 ◽

Vol 40 (2) ◽

pp. e16-e16

Author(s):

I-Lu Lai ◽

Chih-Chien Chou ◽

Po-Ting Lai ◽

Chun-Sheng Fang ◽

Lawrence A Shirley ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Warburg Effect ◽

Glucose Transporter ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells ◽

The Warburg Effect

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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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RETRACTED: Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells

Carcinogenesis ◽

10.1093/carcin/bgu124 ◽

2014 ◽

Vol 35 (10) ◽

pp. 2203-2213 ◽

Cited By ~ 25

Author(s):

I-Lu Lai ◽

Chih-Chien Chou ◽

Po-Ting Lai ◽

Chun-Sheng Fang ◽

Lawrence A Shirley ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Warburg Effect ◽

Glucose Transporter ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells ◽

The Warburg Effect

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Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism

The Journal of Cell Biology ◽

10.1083/jcb.200512100 ◽

2006 ◽

Vol 175 (6) ◽

pp. 913-923 ◽

Cited By ~ 263

Author(s):

Hélène Pelicano ◽

Rui-hua Xu ◽

Min Du ◽

Li Feng ◽

Ryohei Sasaki ◽

...

Keyword(s):

Drug Resistance ◽

Cancer Cells ◽

Mitochondrial Respiration ◽

Warburg Effect ◽

Survival Advantage ◽

Mitochondrial Dna Deletion ◽

Atp Production ◽

Akt Activation ◽

Survival Pathway ◽

The Warburg Effect

Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition with other cells and eventually develop drug resistance is a long-standing paradox. We report that mitochondrial respiration defects lead to activation of the Akt survival pathway through a novel mechanism mediated by NADH. Respiration-deficient cells (ρ-) harboring mitochondrial DNA deletion exhibit dependency on glycolysis, increased NADH, and activation of Akt, leading to drug resistance and survival advantage in hypoxia. Similarly, chemical inhibition of mitochondrial respiration and hypoxia also activates Akt. The increase in NADH caused by respiratory deficiency inactivates PTEN through a redox modification mechanism, leading to Akt activation. These findings provide a novel mechanistic insight into the Warburg effect and explain how metabolic alteration in cancer cells may gain a survival advantage and withstand therapeutic agents.

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Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy

Cancer Control ◽

10.1177/10732748211041243 ◽

2021 ◽

Vol 28 ◽

pp. 107327482110412

Author(s):

Karolina Kozal ◽

Paweł Jóźwiak ◽

Anna Krześlak

Keyword(s):

Glucose Metabolism ◽

Cancer Therapy ◽

Cancer Cells ◽

Warburg Effect ◽

Metabolic Reprogramming ◽

Metabolic Phenotype ◽

Metabolic Adaptation ◽

Drug Bioavailability ◽

Altered Glucose ◽

The Warburg Effect

In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted from mitochondrial damage, multiple studies of the subject revealed a precise, multistage process rather than a random pattern. The phenomenon of aerobic glycolysis emerges not only from mitochondrial abnormalities common in cancer cells, but also results from metabolic reprogramming beneficial for their sustenance. The Warburg effect enables metabolic adaptation of cancer cells to grow and proliferate, simultaneously enabling their survival in hypoxic conditions. Altered glucose metabolism of cancer cells includes, inter alia, qualitative and quantitative changes within glucose transporters, enzymes of the glycolytic pathway, such as hexokinases and pyruvate kinase, hypoxia-inducible factor, monocarboxylate transporters, and lactate dehydrogenase. This review summarizes the current state of knowledge regarding inhibitors of cancer glucose metabolism with a focus on their clinical potential. The altered metabolic phenotype of cancer cells allows for targeting of specific mechanisms, which might improve conventional methods in anti-cancer therapy. However, several problems such as drug bioavailability, specificity, toxicity, the plasticity of cancer cells, and heterogeneity of cells in tumors have to be overcome when designing therapies based on compounds targeted in cancer cell energy metabolism.

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