Warburg Effect or Reverse Warburg Effect? A Review of Cancer MetabolismXu X.D.a · Shao S.X.a · Jiang H.P.b · Cao Y.W.a · Wang Y.H.a · Yang X.C.a · Wang Y.L.a · Wang X.S.a · Niu H.T.a
aThe Key Laboratory of Urology, Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China; bDepartment of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Cancer is a major threat to human health. A considerable amount of research has focused on elucidating the nature of cancer from its pathogenesis to treatment and prevention. Tumor cell metabolism has been considered a hallmark of cancer. Cancer cells differ from normal cells through unlimited cell division, and show a greater need for energy for their rapid growth and duplication. Research on glycometabolism, as the key point of energy metabolism, has played a unique role. In the 1920s, Warburg found that cancer cells prefer to produce adenosine triphosphate (ATP) by glycolysis, which is a less efficient pathway compared to oxidative phosphorylation. This striking discovery, called ‘the Warburg effect', has influenced and guided the study of the mechanism and treatment of tumors for generations, but its causal relationship with cancer progression is still unclear. Some studies have now shown contradicting evidence and a new hypothesis, the reverse Warburg effect, has been put forward, in which cancer cells produce most of their ATP via glycolysis, even under aerobic conditions. In this review we discuss the new points concerning the energy metabolism of a tumor, as well as the current facts and perspectives.
© 2015 S. Karger GmbH, Freiburg
Warburg O: The metabolism of carcinoma cells. J Cancer Res1925;9:148-163.
Cori CF, Cori GT: The carbohydrate metabolism of tumors II. Changes in the sugar, lactic acid, and CO2-combining power of blood passing through a tumor. J Biol Chem 1925;65:397-405.
Warburg O, Minami S: Tests on surviving carcinoma cultures. Biochem Z 1923;142:317-333.
- Gatenby RA, Gillies RJ: Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004;4: 891-899.
- Ferreira LMR: Cancer metabolism: The Warburg effect today. Exp Mol Pathol 2010;89:372-380.
- Pauwels EK, Sturm EJ, Bombardieri E, et al.: Positron-emission tomography with [18F]fluorodeoxyglucose. Part I. Biochemical uptake mechanism and its implication for clinical studies. J Cancer Res Clin Oncol 2000;126:549-559.
- Hsu PP, Sabatini DM: Cancer cell metabolism: Warburg and beyond. Cell 2008;134:703-707.
- Stern R, Shuster S, Neudecker BA, Formby B: Lactate stimulates fibroblast expression of hyaluronan and CD44:the Warburg effect revisited. Exp Cell Res 2002;276:24-31.
- Fischer K, Hoffmann P, Voelkl S, et al.: Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007;109: 3812-3819.
- Erecińska M, Deas J, Silver IA: The effect of pH on glycolysis and phosphofructokinase activity in cultured cells and synaptosomes. J Neurochem 1995;65:2765-2772.
- Lopez-Lazaro M: The Warburg effect: Why and how do cancer cells activate glycolysis in the presence of oxygen? Anticancer Agents Med Chem 2008;8:305-312.
- Samudio I, Fiegl M , Andreeff M: Mitochondrial uncoupling and the Warburg effect: Molecular basis for the reprogramming of cancer cell metabolism. Cancer Res 2009;69:2163-2166.
- Derdak Z, Mark NM, Beldi G, et al.: The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells. Cancer Res 2008;68:2813-2819.
- Weinhouse S: On respiratory impairment in cancer cells. Science 1956;124:267-269.
- Zhou Y, Liu S: 64Cu-labeled phosphonium cations as PET radiotracers for tumor imaging. Bioconjug Chem 2011;22:1459-1472.
- Lieberman BP, Ploessl K, Wang L, et al.: PET imaging of glutaminolysis in tumors by 18F-(2S, 4R) 4-fluoroglutamine. J Nucl Med 2011;52:1947-1955.
- Zu XL, Guppy M: Cancer metabolism: Facts, fantasy, and fiction. Biochem Biophys Res Commun 2004;313:459-465.
- Martinez-Outschoorn UE, Lin Z, Trimmer C, et al.: Cancer cells metabolically' fertilize' the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: Implications for PET imaging of human tumors. Cell Cycle 2011;10:2504-2520.
- Mandujano-Tinoco EA, Gallardo-Pérez JC, Marín-Hernández A, et al.: Anti-mitochondrial therapy in human breast cancer multi-cellular spheroids. Biochim Biophys Acta 2013;1833:541-551.
- Mazurek S, Eigenbrodt E: The tumor metabolome. Anticancer Res 2003;23:1149-1154.
- Fan TWM, Kucia M, Jankowski K, et al.: Rhabdomyosarcoma cells show an energy producing anabolic metabolic phenotype compared with primary myocytes. Mol Cancer 2008;7:79.
- Dang L, Jin S, Su SM: Mutations in glioma and acute myeloid leukemia. Trends Mol Med 2010;16:387-397.
- Mullen AR, Wheaton WW, Jin ES, et al.: Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 2011;481:385-388.
- Scandurra FM, Gnaiger E: Cell respiration under hypoxia: Facts and artefacts in mitochondrial oxygen kinetics. Adv Exp Med Biol 2010;662:7-25.
- Horan AD, Koch CJ: The Km for radiosensitization of human tumor cells by oxygen is much greater than 3 mmHg and is further increased by elevated levels of cysteine. Radiat Res 2001;156:388-398.
- Erickson K, Braun RD, Yu D, et al.: Effect of longitudinal oxygen gradients on effectiveness of manipulation of tumor oxygenation. Cancer Res 2003;63:4705-4712.
- Kobayashi S, Millhorn DE: Hypoxia regulates glutamate metabolism and membrane transport in rat PC12 cells. J Neurochem 2001;76:1935-1948.
- Rodríguez‐Enríquez S, Gallardo‐Pérez JC, Avilés-Salas A, et al.: Energy metabolism transition in multi‐cellular human tumor spheroids. J Cell Physiol 2008;216:189-197.
- Rodríguez-Enríquez S, Carreño-Fuentes L, Gallardo‐Pérez JC, et al.: Oxidative phosphorylation is impaired by prolonged hypoxia in breast and possibly in cervix carcinoma. Int J Biochem Cell B 2010;42:1744-1751.
- Rodríguez-Enríquez S, Hernández-Esquivel L, Marín-Hernández A, et al.: Molecular mechanism for the selective impairment of cancer mitochondrial function by a mitochondrially targeted vitamin E analogue. Biochim Biophys Acta 2012;1817:1597-1607.
- Manalo DJ, Rowan A, Lavoie T, et al.: Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 2005;105:659-669.
- Mandujano-Tinoco EA, Gallardo-Pérez JC, Marín-Hernández A, et al.: Anti-mitochondrial therapy in human breast cancer multi-cellular spheroids. Biochim Biophys Acta 2013;1833: 541-551.
- Marín-Hernández A, Gallardo-Pérez JC, López-Ramírez SY, et al.: Casiopeina II-gly and bromopyruvate inhibition of tumor hexokinase, glycolysis and oxidative phosphorylation. Arch Toxicol 2012;86:753-766.
- Marín-Hernández A, Gracia-Mora I, Ruiz-Ramírez L, Moreno-Sánchez R: Toxic effects of copper-based anti-neoplastic drugs (Casiopeinas) on mitochondrial functions. Biochem Pharmacol 2003;65:1979-1989.
- Hernández-Esquivel L, Marín-Hernández A, Pavón N, et al.: Cardiotoxicity of copper-based anti-neoplastic drugs casiopeinas is related to inhibition of energy metabolism. Toxicol Appl Pharmacol 2006;212:79-88.
- Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J: Cancer: A systems biology disease. Biosystems 2006;83:81-90.
- Hornberg JJ, Bruggeman FJ, Bakker BM, Westerhoff HV: Metabolic control analysis to identify optimal drug targets. Prog Drug Res. 2007;64:171,173-189.
- Moreno-Sánchez R, Saavedra E, Rodríguez-Enríquez S, et al.: Metabolic control analysis indicates a change of strategy in the treatment of cancer. Mitochondrion 2010;10:626-639.
- Murabito E, Smallbone K, Swinton J, et al.: A probabilistic approach to identify putative drug targets in biochemical networks. J R Soc Interface 2011;8:880-895.
- Rodrı́guez-Enrı́quez S, Torres-Márquez ME, Moreno-Sánchez R: Substrate oxidation and ATP supply in AS-30D hepatoma cells. Arch Biochem Biophys 2000;375:21-30.
- Dalmonte ME, Forte E, Genova ML, et al.: Control of respiration by cytochrome c oxidase in intact cells role of the membrane potential. J Biol Chem 2009;284:32331-32335.
- Quarato G, Piccoli C, Scrima R, Capitanio N: Variation of flux control coefficient of cytochrome c oxidase and of the other respiratory chain complexes at different values of protonmotive force occurs by a threshold mechanism. Biochim Biophys Acta 2011;1807:1114-1124.
- Kaambre T, Chekulayev V, Shevchuk I, et al.: Metabolic control analysis of cellular respiration in situ in intraoperational samples of human breast cancer. J Bioenerg Biomembr 2012;44:539-558.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.