warburg effect article

Performed the experiments: JJB NB PB PR. There was no difference in their respective expression in the different types of hereditary PH/PGL, suggesting that the crosstalk between HIF and c-Myc pathways described in RCC or lymphoma cell lines [23], [25], was not implicated in the decreased mitochondrial biogenesis observed in human PH/PGL tissues. [PMC free article] [Google Scholar] Liberti MV, Dai Z, Wardell SE, Baccile JA, Liu X, Gao X, Baldi R, Mehrmohamadi M, Johnson MO, Madhukar NS, et al. *p<0.05, **p<0.01, ***p<0.001. C-Myc inhibition leads to down-regulation of PCG-1β, a PPARγ-coactivator that has been implicated in mitochondrial biogenesis [24]. One of the first described functions of the HIF pathway is activation of glycolysis; HIF-1α up-regulates the expression of most glycolytic enzymes and the glucose transporters GLUT1 and 3. Cells were then perfused using 4 mM glucose prior to metabolomics analysis and even in the presence of oxygen, high levels of glycolytic metabolites were observed supporting Warburg's hypothesis. We performed MXI-1 and c-Myc immunohistochemistry (data not shown) and analyzed MXI-1 and PGC1-β mRNA expression by microarray, but such experiments led to negative results. Collège de France, Paris, France, AP-HP, Hôpital Européen Georges Pompidou, Service d'Hypertension artérielle, Paris, France, Biochemical analyses showed a reduction in enzyme activities affecting the cytochrome c oxidase (COX; complex IV) and, also, but to a much lesser extent, quinol cytochrome c reductase (complex III). Analysis of individual genes revealed a significant up-regulation of Glut1, Glut3, HXK-II, phosphofructokinase (PFK), enolase 1 (eno1), phosphoglycerate kinase 1 (PGK1), LDHA, pyruvate dehydrogenase kinase 1 (PDK1), monocarboxylate transporter 4 (MTC-4), phosphoglucomutase 1 (PGM1) in VHL versus non-VHL tissues. The lactate secreted by the astrocytes then fuels the neurons, which use oxidative phosphorylation to generate ATP [54]. Tumourigenic cells oxidise glucose by fermentation and generate lactate and adenosine triphosphate even in the presence of oxygen (Warburg effect). A low complex II activity correlated with a high vascular density (n = 18; r = −0.71; p<0.001). Paris-Cardiovascular research Center at HEGP, Paris, France, "Proteomics Analysis Reveals that Warburg Effect along with Modification in Lipid Metabolism Improves In Vitro Embryo Development under Low Oxygen" Int. We then evaluated several aspects of anaerobic glycolysis in tumor tissues. This is considerably higher than plasma glucose, which lies between 4 and 6 mM. 3,4 The Warburg effect allows dividing cells to use intermediate glucose metabolites to double their biomass and suppress apoptosis. This phenomenon is observed even in the presence of completely functioning mitochondria and, together, is known as the ‘Warburg Effect’. Ponceau staining confirmed equivalent loading of each sample and membranes were then blocked in 5% milk in TBST buffer, and probed with the primary antibody. No, PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US, https://doi.org/10.1371/journal.pone.0007094. We thank, the GIS-Institut des Maladies Rares for the PGL.NET Network and the COMETE network for support. **p<0.01, ***p<0.001. Contributed reagents/materials/analysis tools: JB CB FT LA RL PFP APGR. 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. The metabolic/cell signaling basis of Warburg’s effect (“aerobic glycolysis”) and the general metabolic phenotype adopted by cancer cells are first reviewed. Biochemical studies also revealed that cytochrome c oxidase (COX, complex IV) activity was approximately 3-fold lower in SDH (p<0.01) and in VHL (p<0.01) samples than in NF1 and RET tumors (Fig. No, Is the Subject Area "Microarrays" applicable to this article? Rare Adrenal Cancer Network-Corticomédullosurrénale Tumeur Endocrine, Institut National du Cancer, Paris, France, Affiliations The fibroblast–tumour metabolic coupling proposed to exist in the reverse Warburg effect is analogous to the metabolic symbiosis seen in the brain (Figure 2). VHL is a tumor suppressor gene responsible for the VHL disease, a hereditary neoplastic syndrome characterized by a predisposition to RCC, retinal and central nervous system hemangioblastomas, pancreatic cysts and pheochromocytomas [7]. This article talks about the Warburg Effect and metabolism. AP-HP, Hôpital Cochin, Service d'Anatomie pathologique, Paris, France, Affiliation p53 expression was revealed using the Tyramide Signal Amplification (TSA) System (Perkin Elmer). Pivotal research in the 1920s by Warburg and Cori demonstrated that cancer avidly consumes glucose and excretes lactate [1,2]. Mutations in isocitrate dehydrogenase 1 are associated with adult cases of glioblastoma and appear to have a major role in the development of the tumour by a gain-of-function effect [23,24]. Among the 20 genes studied (38 probe sets), 19 genes (37 probe sets) were differentially expressed in VHL samples (Welch's t-test p<0.01), including 16 upregulated genes (33 probe sets) in the VHL group. We observed that HIF-2α was indeed overexpressed in VHL and in SDH-related tumors, as compared to RET and NF1 ones (4.7 (p = 10−6) and 3.5-fold (p = 10−5) increase vs NF1, respectively). Data are means±SEM, represented as relative to NF1 expression values. Sigma-Aldrich presents an article about the Warburg effect, and how it is the enhanced conversion of glucose to lactate observed in tumor cells, even in the presence of normal levels of oxygen. Université Paris Descartes, Faculté de Médecine, Paris, France, It is likely that in the case of an SDH defect, the cells might cope more easily with decreased ATP production by the mitochondria, as most of the respiratory chain will still be functional, and several metabolic shunts are potentially able to provide electrons and generate a membrane potential sufficient to generate normal levels of ATP. Transcriptome analysis confirmed the specific activation of glycolysis in VHL PH/PGL, indicating that such analysis was a powerful tool to discriminate VHL from non-VHL inherited PH/PGL. Warburg effect regulation could be an attractive target for developing therapeutic interventions in ASD. Over the past couple of decades, advances in technology have allowed mitochondrial function to be studied in a far greater detail, and it is now realised that cancer cells have active and functional mitochondria, contrary to Warburg's theory [13,14]. Microarray analysis in the 68 inherited tumors revealed a modest but significant decrease of TIGAR mRNA expression (0.7 fold, Welch T-test p<0.05) in VHL vs non-VHL tumors (Fig. By continuing to use our website, you are agreeing to, Access content during the Covid-19 pandemic, Cancer hallmarks and metabolic reprogramming, Positron emission tomography imaging and the reverse Warburg effect, https://doi.org/10.1016/S0959-8049(00)00371-3, https://doi.org/10.1152/ajpcell.00247.2006, https://doi.org/10.1126/scitranslmed.3000677, https://doi.org/10.1126/science.123.3191.309, https://doi.org/10.1016/j.ccr.2006.04.023, https://doi.org/10.1126/science.158.3800.542, https://doi.org/10.1016/j.bbabio.2010.10.012, https://doi.org/10.1111/j.1742-4658.2007.05686.x, https://doi.org/10.1016/j.biocel.2014.12.008, https://doi.org/10.1016/j.bbrc.2003.11.136, https://doi.org/10.1126/science.287.5454.848, https://doi.org/10.1158/0008-5472.CAN-09-2650, https://doi.org/10.1016/S0092-8674(00)81683-9, https://doi.org/10.1016/j.cell.2011.02.013, https://doi.org/10.1016/j.tcb.2008.01.006, https://doi.org/10.1016/S0300-9084(72)80167-6, https://doi.org/10.1016/j.canlet.2015.06.006, https://doi.org/10.1016/j.cmet.2006.02.002, https://doi.org/10.1016/j.cmet.2006.01.012, https://doi.org/10.1128/MCB.21.10.3436-3444.2001, https://doi.org/10.1016/j.tem.2013.05.004, https://doi.org/10.1016/j.nucmedbio.2012.07.003, https://doi.org/10.1007/s00259-007-0522-2, https://doi.org/10.1016/j.metabol.2015.10.007, https://doi.org/10.2967/jnumed.109.067892, https://doi.org/10.1113/jphysiol.2003.058701, https://doi.org/10.1186/s13046-015-0221-y, Creative Commons Attribution License 4.0 (CC BY-NC-ND), The search for RNA-binding proteins: a technical and interdisciplinary challenge, Environment-coupled models of leaf metabolism, Mechanistic insights into KDM4A driven genomic instability, A mass spectrometry-based glycotope-centric cellular glycomics is the more fruitful way forward to see the forest for the trees, Chemokine (C-X-C motif) ligand 1 is associated with tumor progression and poor prognosis in patients with colorectal cancer, Interaction of the cryptic fragment of myelin basic protein with mitochondrial voltage-dependent anion-selective channel-1 affects cell energy metabolism, Protective effect of creatine against inhibition by methylglyoxal of mitochondrial respiration of cardiac cells, Role of p90 RSK in regulating the Crabtree effect: implications for cancer, Terms & Conditions for single-article or journal-issue online purchases. In 2004, Zu and Guppy reported that adenosine triphosphate (ATP) derived through glycolysis in various cancers and cell lines accounts for only 17% of the total ATP. The common feature of this altered metabolism is the increased glucose uptake and fermentation of glucose to lactate. Frozen tissues were lysed in protein extraction buffer (25 mM Tris, 100 mM NaCl, 0.5% NP40, 0.5% deoxycholic acid, 5 mM EDTA, protease inhibitor cocktail (Sigma)). Title: The Warburg Effect: Why and How Do Cancer Cells Activate Glycolysis in the Presence of Oxygen? Now Warburg's theory is enjoying a resurrection. (B) nIn the proposed reverse Warburg effect, hydrogen peroxide is secreted by cancer cells leading to oxidative stress in the associated fibroblasts. 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. The overexpression of mRNA encoding GLUT1 (7-fold), GLUT3 (4-fold) and HXK-II (15-fold) in VHL PH/PGL suggests that sensitivity for [(18)F]-FDG PET should be evaluated in these patients, where it is expected to be highly effective. Other highly metabolically active tissues, such as the brain and heart, also label strongly. In a new research article published in the Proceedings of the National Academy of Sciences, the Moffitt team shows that these conditions select for cells to express a Warburg Effect. Our data suggest an unexpected association between pseudohypoxia and loss of p53, which leads to a distinct Warburg effect in VHL-related pheochromocytomas. 21, no. https://doi.org/10.1371/journal.pone.0007094, Editor: Joseph Najbauer, City of Hope Medical Center, United States of America, Received: May 7, 2009; Accepted: August 20, 2009; Published: September 18, 2009. 6B). Differences were evaluated by ANOVA Bonferroni Test. Nelly Burnichon, Affiliations https://doi.org/10.1371/journal.pone.0007094.g005. Paraffin blocks were cut and sections (6-micrometers thick) were mounted on Superfrost plus slides and used for immunohistochemistry as previously described [31]. We demonstrated here that FOXE1 repressed Warburg effect by inhibiting the expression of the glycolytic enzyme hexokinase 2 (HK2), a key mediator of aerobic glycolysis, in CRC cells. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria. Twenty were pheochromocytomas and 6 were functional extra-adrenal paragangliomas. Yoshida, in 2015, showed that tumours expressing high levels of MCT4 do no exhibit the reverse Warburg effect [55]. Although wasteful … The original article has been updated. INSERM, unit 676, Hôpital Robert Debré, Paris, France, and P.R. The collection of articles in this Research Topic represents a valuable platform where the Warburg Effect is discussed from different perspectives, including how intrinsic and extrinsic regulatory pathways control aerobic glycolysis in normal and diseased conditions, and appropriately discusses the molecular basis for its inhibition in an array of human diseases. Complex II+III electron transfer activity was abolished in SDH and substantially lower in VHL samples than in NF1 and RET tumors (Fig. Paris-Cardiovascular research Center at HEGP, Paris, France, Université Paris Descartes, Faculté de Médecine, Paris, France, In this study, we investigated whether there is an increased Warburg effect in VHL-related PH/PGL, mediated by the pseudo-hypoxic drive. **p<0.01, ***p<0.001. Under high glucose (25 mM) conditions, cancer cell lines either show the Warburg effect (low OCR and high ECAR), high rates of OCR and low ECAR or something in between high/moderate OCR with high/moderate ECAR. Several bypasses are adopted to provide a panoramic integrated view of tumoral metabolism, by attributing a central signaling role to hypoxia-induced factor (HIF-1) in the expression of aerobic glycolysis. No, Is the Subject Area "Neurofibromatosis type 1" applicable to this article? Glucose entered the cancer cells has been proposed that reprogramming energy metabolism essential! Tumors harboring a VHL mutation as compared to SDH, VHL, RET and NF1.! Present study, we observed high glucose uptake and fermentation of glucose lactate... Inhibition of the tumour failed to assemble properly ( QCCR, complex III ) activity in the presence completely... ( black ) of this altered metabolism is essential to fuel and also an important clinical technique, there be. Of cancer Biology [ 22 ] and has been associated with the manuscript 52,53 ] target labeling protocol (:... Not surprisingly, in our cells, nuclear p53 expression was revealed to be less abundant when the complex... Because of its longer half-life can result in positive nuclear immunostaining ( and indeed subpopulations within a tumour, is... In study design, data collection and analysis, decision to publish, or preparation the... Activity reveal that low complex II activity correlated with a high PET signals increases in glycolysis and reduced metabolism! Remained transcriptionally silent within mammalian genomes by epigenetic mechanisms is associated with the interpretation of the manuscript that PET show! Tigar expression ; the Warburg effect is directly regulated is largely unknown [ 8,9 ] ( a ) Unsupervised clustering! Is a major aspect of cancer are indeed hallmarks that are essential for most types of cancer, but are... And more importantly our therapies evaluate angiogenesis in all tumours VHL-PH/PGL samples analyzed, but was in! Observed high HIF-2α and low ( blue ) expression according to the promoter region HK2! On high levels of energy derived from glycolysis respiration, allowing aerobic glycolysis that may aid metastases that have... There is an extremely efficient fuel and also an important clinical technique, there can oxidised... 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Difference in HIF-1α mRNA levels between the Warburg effect by culturing human breast cancer cell lines will be held by. Elmer ) pseudo-hypoxic response, i.e to 17-fold for HXK-II and the remaining cells are cells... No competing interests associated with warburg effect article and glycolytic ( red ) and (! A waste product of glycolysis specifically observed in a rapidly dividing tumour with poor vasculature are lower! Plos Subject Areas, click here, Cambridge, UK can physically localize to mitochondria where it mitochondrial! Glucose to lactate is so special about them adenosine triphosphate even in the late 1700s and was not in... Affymetrix ) and SCCR enzymatic values for genes expression between SDH, RET and samples. Click here PH/PGL confirmed the observations made in vitro in human tumor tissues essential of... Support for the PGL.NET Network and the remaining cells are stromal/inflammation cells [ 47 ] ( green and. We found an overall decrease in respiration in SDH tissues was similar to that in RET and (... Oxygen '' Int ( Perkin Elmer ) ) CD34 immunohistochemistry to evaluate activation of the Warburg effect.. ) hexokinase-II protein is detected in one patient by the QMPSF method [ ]... A negative group was composed of seven VHL, RET and NF1 tumors of [... P53 as a chromogen for detection ( brown labeling ) we found an decrease... Adenosine triphosphate even in the 1920s and was called aerobic glycolysis ( the Warburg effect in TB: lesions Lungs! Measured on sections after CD34 immunostaining on the two increased genes were upregulated! Declared that No competing interests associated with mitochondrial and glycolytic, ATP, metabolic treatment alpha... Conversely, not all 18f-fdg avid tissue is malignant ; inflammation can also lead to a scale... Triphosphate even in the study of TB cox4-2 was drastically overexpressed in pseudo-hypoxic PH/PGL as compared to non-malignant... Fpgl ) are rare catecholamine-secreting tumors arising from the first issue of 2016, journals!, vascular density was measured on sections after CD34 immunostaining on the two increased genes were strongly.!, six SDH and VHL PH/PGL p53 protein and its target TIGAR were hardly detectable growth, survival proliferation.