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Principles of the Warburg Effect and Cancer Cell Metabolism

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Molecular mechanisms and physiology of disease

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Abstract

The implication of cancer metabolism is gaining recent interest in cancer research after nearly nine decades since Dr. Otto Warburg first discovered the differing metabolic pathway of cancer cells. His early observations established that in contrast to normal cellular metabolism, most cancer cells rely on aerobic glycolysis. Although aerobic glycolysis is inefficient with respect to production of ATP it may provide a selective advantage for cancer cells producing glycolytic intermediates to support cell growth and division. It is becoming evident that genetic alterations associated with cancer have a role to play in aberrant cellular metabolism. In this chapter we discuss the current concepts of cancer metabolism and the relationship to tumor suppressor genes and oncogenes. The widespread recognition of the complex interplay between genetic alterations, cellular metabolism, and the tumor microenvironment could establish a framework for exploitable cancer therapies and potential targets of therapeutic intervention. In this chapter we outline these prospects.

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Abbreviations

AKT:

A serine/threonine protein kinase named AKT

AMPK:

5′ AMP-activated protein kinase

ATP:

Adenosine triphosphate

EPO:

Erythropoietin

GADD45A:

Growth arrest and DNA-damage-inducible protein

GsH:

Glutathione

HIF-1:

Hypoxia-inducible factor 1

IGF-IBP-3:

Insulin-like growth factor binding protein 3

LDHA:

Lactate dehydrogenase A

mTOR:

Mammalian target of rapamycin

NADPH:

Nicotinamide adenine dinucleotide phosphate

p53:

Tumor protein 53

PDGFB:

Platelet-derived growth factor subunit B

PI3K:

Phosphoinositide-3-kinase

PKM2:

Pyruvate kinase isozyme M2

PTEN:

Phosphatase and tensin homolog

RAS:

Reticular activating system

SCO2:

Synthesis of cytochrome c oxidase subunit 2

TCA:

Tricarboxylic acid

TSC-2:

Tuberous sclerosis complex 2

VEGF-A:

Vascular endothelial growth factor A

References

  • Agathocleous M, Love N, Randlett O, Harris J, Liu J, Murray A, Harris W (2012) Metabolic differentiation in the embryonic retina. Nat Cell Biol 14:859–864

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Azam F, Mehta S, Harris AL (2010) Mechanisms of resistance to antiangiogenesis therapy. Eur J Cancer 46:1323–1332

    Article  CAS  PubMed  Google Scholar 

  • Barna M (2008) Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 456:971–975

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bensaad K (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120

    Article  CAS  PubMed  Google Scholar 

  • Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bertout JA (2008) The impact of O2 availability on human cancer. Nat Rev Cancer 8:967–975

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Boxer LM, Dang CV (2001) Translocations involving c-myc and c-myc function. Oncogene 20:5595–5610

    Article  CAS  PubMed  Google Scholar 

  • Cairns RA (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11:85–95

    Article  CAS  PubMed  Google Scholar 

  • Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC (2008) Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452:181–186

    Article  CAS  PubMed  Google Scholar 

  • Comerford K, Wallace T, Karhausen J, Louis N, Montalto M, Colgan S (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62:3387–3394

    CAS  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, Semenza GL (1999) Oncogenic alterations of metabolism. Trends Biochem Sci 24:68–72

    Article  CAS  PubMed  Google Scholar 

  • Deberardinis RJ, Cheng T (2010) Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29:313–324

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ebos JM, Lee CR, Kerbel RS (2009) Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 15:5020–5025

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Elstrom R, Bauer D, Buzzai M, Karnauskas R, Harris M, Plas D, Zhuang H, Cinalli R, Alavi A, Rudin C, Thompson C (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64:3892–3899

    Article  CAS  PubMed  Google Scholar 

  • Ferrara N, Hillan K, Gerber H-P, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400

    Article  CAS  PubMed  Google Scholar 

  • Fiske B, Vander Heiden M (2012) Seeing the Warburg effect in the developing retina. Nat Cell Biol 14:790–791

    Article  CAS  PubMed  Google Scholar 

  • Gatenby R, Gillies R (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg R (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  • Huang LE, Gu J, Schau M, Bunn HF (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A 95:7987–7992

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Iritani BM, Eisenman RN (1999) c-Myc enhances protein synthesis and cell size during B lymphocyte development. Proc Natl Acad Sci U S A 96:13180–13185

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jones NP (2012) Targeting cancer metabolism—aiming at a tumour’s sweet-spot. Drug Discov Today 17:232–241

    Article  CAS  PubMed  Google Scholar 

  • Kim JW (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Liao D, Corle C, Seagroves T, Johnson R (2007) Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res 67:563–572

    Article  CAS  PubMed  Google Scholar 

  • Nazarian R, Shi H, Wang Q, Kong X, Koya R, Lee H, Chen Z, Lee M-K, Attar N, Sazegar H, Chodon T, Nelson S, Mcarthur G, Sosman J, Ribas A, Lo R (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Parsons DW, Jones S, Zhang X, Lin J, Leary R, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia G, Olivi A, Mclendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam D, Tekleab H, Diaz L, Hartigan J, Smith D, Strausberg R, Marie SKN, Shinjo SMO, Yan H, Riggins G, Bigner D, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu V, Kinzler K (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schrödinger E (1992) What is life? The physical aspect of the living cell; with, mind and matter; & autobiographical sketches/Erwin Schrödinger. Cambridge University Press, Cambridge

    Book  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Shackelford D, Shaw R (2009) The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9:563–575

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tennant D, Durn R, Gottlieb E (2010) Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10:267–277

    Article  CAS  PubMed  Google Scholar 

  • Thomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539–549

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vander Heiden MG (2011) Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10:671–684

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vaughn A, Deshmukh M (2008) Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol 10:1477–1483

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vivanco I, Sawyers C (2002) The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  CAS  PubMed  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310

    Article  CAS  PubMed  Google Scholar 

  • Vousden K, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604

    Article  CAS  PubMed  Google Scholar 

  • Wang GL, Semenza GL (1993) Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 268:21513–21518

    CAS  PubMed  Google Scholar 

  • Warburg O (1924) Ãœber den Stoffwechsel der Carcinomzelle. Naturwissenschaften 12:1131

    Article  CAS  Google Scholar 

  • Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  CAS  PubMed  Google Scholar 

  • Wong K-K, Engelman J, Cantley L (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20:87–90

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

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.

Author information

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

    Natalie Molino B.Sc., K. Ververis B.Sc. (Hons.) & Tom C. Karagiannis B.Sc. (Hons.), Ph.D.

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

    Natalie Molino B.Sc., K. Ververis B.Sc. (Hons.) & Tom C. Karagiannis B.Sc. (Hons.), Ph.D.

Authors
  1. Natalie Molino B.Sc.
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  2. K. Ververis B.Sc. (Hons.)
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  3. Tom C. Karagiannis B.Sc. (Hons.), Ph.D.
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Corresponding author

Correspondence to Tom C. Karagiannis B.Sc. (Hons.), Ph.D. .

Editor information

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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Molino, N., Ververis, K., Karagiannis, T.C. (2014). Principles of the Warburg Effect and Cancer Cell Metabolism. 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_12

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