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Molecular mechanisms and physiology of disease pp 371–382Cite as

Molecular Aspects of the Warburg Effect

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Abstract

The Warburg effect is a quality of cancer cells which is so defining of them that it is considered an important emerging hallmark of disease. Discovered by Dr. Otto Warburg in the 1920s, it was not until the last decade that the importance of this phenomenon was more widely realised and exploited in medical research, and its future possibilities conceived, largely due to an increase in our understanding of cellular metabolism. The Warburg effect itself is an observed change in the metabolism of cancer cells, where they metabolise a much larger amount of glucose than normal cells, utilising aerobic glycolysis rather than oxidative phosphorylation. While aerobic glycolysis creates less ATP energy for the cell it creates metabolic products, which allows the tumour to increase its biomass, important for the growth of the tumour and its ability to metastasize. Although it is still unknown why this metabolic change occurs, it is driven, at least in part, by the actions of activated oncogenes, in particular HIF-1α, and suppression of tumour suppressor proteins, such as p53. This quality provides the basis for the cancer monitoring technique of positron emission tomography, and there are emerging drugs which take advantage of this change from normal cells for potential therapeutic benefits. For example, metabolic drugs such as the type II diabetes drug metformin are being investigated and trialled as tools to starve cancer cells of their large energy requirements. In this chapter we provide an outline of the molecular characteristics of the Warburg effect and discuss related potential therapeutic developments.

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References

  • Adekola K, Rosen ST, Shanmugam M (2012) Glucose transporters in cancer metabolism. Curr Opin Oncol 24:650–654

    Article  CAS  PubMed  Google Scholar 

  • Alirol E, Martinou JC (2006) Mitochondria and cancer: is there a morphological connection? Oncogene 25:4706–4716

    Article  CAS  PubMed  Google Scholar 

  • Barron C, Tsiani E, Tsakiridis T (2012) Expression of the glucose transporters GLUT1, GLUT3, GLUT4 and GLUT12 in human cancer cells. BMC Proc 6:1

    Article  Google Scholar 

  • Bayley JP, Devilee P (2012) The Warburg effect in 2012. Curr Opin Oncol 24:62–67

    Article  CAS  PubMed  Google Scholar 

  • Boonstra J, Post JA (2004) Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells. Gene 337:1–13

    Article  CAS  PubMed  Google Scholar 

  • Busk M, Horsman MR, Jakobsen S, Bussink J, Van Der Kogel A, Overgaard J (2008) Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage. Eur J Nucl Med Mol Imaging 35:2294–2303

    Article  CAS  PubMed  Google Scholar 

  • Chaneton B, Gottlieb E (2012) Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer. Trends Biochem Sci 37:309–316

    Article  CAS  PubMed  Google Scholar 

  • Chen J-Q, Russo J (2012) Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta 1826:370–384

    CAS  PubMed  Google Scholar 

  • Chiaradonna F, Moresco RM, Airoldi C, Gaglio D, Palorini R, Nicotra F, Messa C, Alberghina L (2012) From cancer metabolism to new biomarkers and drug targets. Biotechnol Adv 30:30–51

    Article  CAS  PubMed  Google Scholar 

  • Dang CV (2010) Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res 70:859–862

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dang C (2012) Links between metabolism and cancer. Genes Dev 26:877–890

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dang CV, Kim J-W, Gao P, Yustein J (2008) The interplay between MYC and HIF in cancer. Nat Rev Cancer 8:51–56

    Article  CAS  PubMed  Google Scholar 

  • Deberardinis RJ (2008) Is cancer a disease of abnormal cellular metabolism? New angles on an old idea. Genet Med 10:767–777

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Diaz-Ruiz R, Rigoulet M, Devin A (2011) The Warburg and Crabtree effects: on the origin of cancer cell energy metabolism and of yeast glucose repression. Biochim Biophys Acta 1807:568–576

    Article  CAS  PubMed  Google Scholar 

  • Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95

    CAS  PubMed  Google Scholar 

  • Falasca M (2010) PI3K/Akt signalling pathway specific inhibitors: a novel strategy to sensitize cancer cells to anti-cancer drugs. Curr Pharm Des 16:1410–1416

    Article  CAS  PubMed  Google Scholar 

  • Ferguson E, Rathmell J (2009) New roles for pyruvate kinase M2: working out the Warburg effect. Trends Biochem Sci 33:359–362

    Article  Google Scholar 

  • Fiske VH (2012) Seeing the Warburg effect in the developing retina. Nat Cell Biol 14:790–791

    Article  CAS  PubMed  Google Scholar 

  • Gallagher BM, Fowler JS, Gutterson NI, Macgregor RR, Wan CN, Wolf AP (1978) Metabolic trapping as a principle of oradiopharmaceutical design: some factors responsible for the biodistribution of [18F] 2-deoxy-2-fluoro-D-glucose. J Nucl Med 19:1154–1161

    CAS  PubMed  Google Scholar 

  • Ganapathy V, Thangaraju M, Prasad PD (2009) Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther 121:29–40

    Article  CAS  PubMed  Google Scholar 

  • Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V et al (2007) HIF dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12:230–238

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22

    Article  CAS  PubMed  Google Scholar 

  • Hamanaka R, Chandel N (2011) Warburg effect and redox balance. Science 334:1219–1220

    Article  CAS  PubMed  Google Scholar 

  • Harris A (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47

    Article  CAS  PubMed  Google Scholar 

  • Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134:703–707

    Article  CAS  PubMed  Google Scholar 

  • Kaelin W (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682

    Article  CAS  PubMed  Google Scholar 

  • Kim J, Dang C (2006) Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res 66:8927–8930

    Article  CAS  PubMed  Google Scholar 

  • Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11:325–337

    Article  CAS  PubMed  Google Scholar 

  • Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13:472–482

    Article  CAS  PubMed  Google Scholar 

  • Krzeslak A, Jozwiak P, Forma E, Brys M, Wozniak P, Wikosz J, Lipinski M, Rozanski W (2012a) Diagnostic value of glucose transporter 1 and 3 (GLUT1 and GLUT3) mRNA level in postmenopausal women with urinary bladder cancer. Przegl Menopauzalny 3:178–182

    Google Scholar 

  • Krzeslak A, Wojcik-Krowiranda K, Forma E, Jozwiak P, Romanowicz H, Bienkiewicz A, Brys M (2012b) Expression of GLUT1 and GLUT3 glucose transporters in endometrial and breast cancers. Pathol Oncol Res 18:721–728

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kwee T, Basu S, Saboury B, Ambrosini V, Torigian D, Alavi A (2011) A new dimension of FDG-PET interpretation: assessment of tumor biology. Eur J Nucl Med Mol Imaging 38:1158–1170

    Article  PubMed  Google Scholar 

  • Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, Emionite L, De Cabo R, Longo VD (2012) Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med 4:124ra27

    PubMed Central  PubMed  Google Scholar 

  • Levine A (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331

    Article  CAS  PubMed  Google Scholar 

  • Levine A, Puzio-Kuter A (2010) The control of the metabolic switch in cancers by oncogenes and tumour suppressor genes. Science 330:1340–1344

    Article  CAS  PubMed  Google Scholar 

  • Li J, Shi M, Cao Y, Yuan W, Pang T, Li B, Sun Z, Chen L, Zhao RC (2006) Knockdown of hypoxia-inducible factor-1alpha in breast carcinoma MCF-7 cells results in reduced tumor growth and increased sensitivity to methotrexate. Biochem Biophys Res Commun 342:1341–1351

    Article  CAS  PubMed  Google Scholar 

  • Locasale J, Cantley L, Vander Heiden M (2009) Cancer’s insatiable appetite. Nature 27:916–917

    CAS  Google Scholar 

  • Lucignani G, Larson SM (2010) Doctor, what does my future hold? The prognostic value of FDG-PET in solid tumours. Eur J Nucl Med Mol Imaging 37:1032–1038

    Article  PubMed  Google Scholar 

  • Luo W, Semenza G (2012) Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol Metab 23:560–566

    Article  PubMed Central  PubMed  Google Scholar 

  • Macheda MEA (2005) Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 202:654–662

    Article  CAS  PubMed  Google Scholar 

  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275

    Article  CAS  PubMed  Google Scholar 

  • Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Activation of the HIF pathway in cancer. Curr Opin Genet Dev 11:293–299

    Article  CAS  PubMed  Google Scholar 

  • Medina RA, Owen GI (2002) Glucose transporters: expression, regulation and cancer. Biol Res 35:9–26

    Article  CAS  PubMed  Google Scholar 

  • Medina RA, Southworth R, Fuller W, Garlick PB (2002) Lactate-induced translocation of GLUT1 and GLUT4 is not mediated by phosphatidylinositol-3-kinase pathway in the rat heart. Basic Res Cardiol 97:168–176

    Article  CAS  PubMed  Google Scholar 

  • Mendez O, Zavadil J, Esencay M, Lukyanov Y, Santovasi D, Wang SC, Newcomb EW, Zagzag D (2010) Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres. Mol Cancer 9:133

    Article  PubMed Central  PubMed  Google Scholar 

  • Milane L, Duan Z, Amiji M (2011a) Role of hypoxia and glycolysis in the development of multi-drug resistance in human tumor cells and the establishment of an orthotopic multi-drug resistant tumor model in nude mice using hypoxic pre-conditioning. Cancer Cell Int 11:3

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Milane L, Ganesh S, Shah S, Duan Z-F, Amiji M (2011b) Multi-modal strategies for overcoming tumor drug resistance: hypoxia, the Warburg effect, stem cells, and multifunctional nanotechnology. J Control Release 155:237–247

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pedersen PL (2007) The cancer cell’s “power plants” as promising therapeutic targets: an overview. J Bioenerg Biomembr 39:1–12

    Article  CAS  PubMed  Google Scholar 

  • Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11:761–774

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Resendis-Antonio O, Checa A, Encarnación S (2010) Modeling core metabolism in cancer cells: surveying the topology underlying the Warburg effect. PLoS One 5:1–11

    Article  Google Scholar 

  • Rodríguez-Enríquez S, Marín-Hernández A, Gallardo-Pérez JC, Moreno-Sánchez R (2009) Kinetics of transport and phosphorylation of glucose in cancer cells. J Cell Physiol 221:552–559

    Article  PubMed  Google Scholar 

  • Rogers S, Docherty SE, Slavin JL, Henderson MA, Best JD (2003) Differential expression of GLUT12 in breast cancer and normal breast tissue. Cancer Lett 193:225–233

    Article  CAS  PubMed  Google Scholar 

  • Semenza GL (2001) Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 7:345–350

    Article  CAS  PubMed  Google Scholar 

  • Semenza G (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  CAS  PubMed  Google Scholar 

  • Shim H, Dolde C, Lewis BC, Wu C-S, Dang G, Jungmann RA, Dalla-Favera R, Dang CV (1997) c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci U S A 94:6658–6653

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stubbs M, Griffiths JR (2010) The altered metabolism of tumors: HIF-1 and its role in the Warburg effect. Adv Enzyme Regul 50:44–55

    Article  PubMed  Google Scholar 

  • Van Ginkel RJ, Hoekstra HJ, Pruim J, Nieweg OE, Molenaar WM, Paans AM, Willemsen AT, Vaalburg W, Koops HS (1996) FDG-PET to evaluate response to hyperthermic isolated limb perfusion for locally advanced soft-tissue sarcoma. J Nucl Med 37:984–990

    PubMed  Google Scholar 

  • Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Warburg O (1924) Uber den Stoffwechsel der Carcinomzelle. Naturwissenschaften 12:1131–1137

    Article  CAS  Google Scholar 

  • Wenger JB, Chun SY, Dang DYT, Luesch H, Dang LH (2011) Combination therapy targeting cancer metabolism. Med Hypotheses 76:169–172

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wolf A, Agnihotri S, Micallef J, Mukherjee J, Sabha N, Cairns R, Hawkins C, Guha A (2011) Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med 208:313–326

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu R, Pelicano H, Zhou Y, Carew J, Feng L, Bhalla K, Keating M, Huang P (2005) Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 65:613–621

    Article  CAS  PubMed  Google Scholar 

  • Yacovan A, Ozeri R, Kehat T, Mirilashvili S, Sherman D, Aizikovich A, Shitrit A, Ben-Zeev E, Schutz N, Bohana-Kashtan O, Konson A, Behar V, Becker OM (2012) 1-(Sulfonyl)-5-(arylsulfonyl)indoline as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg Med Chem Lett 22:6460–6468

    Article  CAS  PubMed  Google Scholar 

  • Yanagawa T, Watanabe H, Shinozaki T, Takagishi K (2010) Usefulness of FDG PET in primary bone tumors. Open Bone J 2:19–23

    Article  Google Scholar 

  • Yeoa E-J, Chunb Y-S, Parka J-W (2004) New anticancer strategies targeting HIF-1. Biochem Pharmacol 68:1061–1069

    Article  Google Scholar 

  • Yeung SJ, Pan J, Lee MH (2008) Roles of p53, MYC and HIF-1 in regulating glycolysis—the seventh hallmark of cancer. Cell Mol Life Sci 65:3981–3999

    Article  CAS  PubMed  Google Scholar 

  • Yijun C, Cairns R, Papandreou I, Koong A, Denko NC (2009) Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect. PLoS One 4:1–9

    Article  Google Scholar 

  • Zawacka-Pankau J, Grinkevich VV, Hünten S, Nikulenkov F, Gluch A, Li H, Enge M, Kel A, Selivanova G (2011) Inhibition of glycolytic enzymes mediated by pharmacologically activated p53: targeting Warburg effect to fight cancer. J Biol Chem 286:41600–41615

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang X-D, Qin Z-H, Wang J (2010) The role of p53 in cell metabolism. Acta Pharmacol Sin 31:1208–1212

    Article  CAS  PubMed  Google Scholar 

  • Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW (1999) Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 59:5830–5835

    CAS  PubMed  Google Scholar 

  • Zhou M, Zhao Y, Ding Y, Liu H, Liu Z, Fodstad O, Riker AI, Kamarajugadda S, Lu J, Owen LB, Ledoux SP, Tan M (2010) Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol. Mol Cancer 9:33

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The support of the Australian Institute of Nuclear Science and Engineering is acknowledged. T.C.K. was the recipient of AINSE awards. T.C.K. is a Future Fellow and Epigenomic Medicine Laboratory is supported by the Australian Research Council. This work was supported in part by the Victorian Government’s Operational Infrastructure Support Program.

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Authors and Affiliations

  1. Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, 75 Commercial Road, Melbourne, 3004, VIC, Australia

    Elba Balding B.Sc., Katherine Ververis B.Sc. (Hons.) & Tom C. Karagiannis B.Sc. (Hons.), Ph.D.

  2. Department of Pathology, The University of Melbourne, Parkville, VIC, Australia

    Elba Balding B.Sc., Katherine Ververis B.Sc. (Hons.) & Tom C. Karagiannis B.Sc. (Hons.), Ph.D.

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  1. Elba Balding B.Sc.
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  2. Katherine Ververis B.Sc. (Hons.)
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  3. Tom C. Karagiannis B.Sc. (Hons.), Ph.D.
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Correspondence to Tom C. Karagiannis B.Sc. (Hons.), Ph.D. .

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Editors and Affiliations

  1. Department of Surgery Molecular cardiology and Angiogenesis, University of Connecticut School of Medicine, Farmington, Connecticut, USA

    Nilanjana Maulik

  2. Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia

    Tom Karagiannis

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Balding, E., Ververis, K., Karagiannis, T.C. (2014). Molecular Aspects of the Warburg Effect. In: Maulik, N., Karagiannis, T. (eds) Molecular mechanisms and physiology of disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0706-9_13

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