Skip to main content
SpringerLink
Log in
Book cover

New Advances on Disease Biomarkers and Molecular Targets in Biomedicine pp 159–174Cite as

Targeting Cancer Metabolisms

  • Chapter
  • First Online:

  • 1016 Accesses

Abstract

Cancer cells have a different pattern of metabolism compared with that of normal differentiated adult cells. They mainly produce energy in the form of ATP through glycolysis, even in an oxygen-rich condition. And the mitochondrial function is shifted from ATP production to generation of biosynthetic precursors—for example, fatty acid synthesis is increased. Over the last decade, studies have shown that many of the oncogenes and tumor suppressors are directly involved in this metabolic transformation. With the new understanding in cancer metabolism, the cellular metabolic reprogramming should no longer be viewed as an indirect response to tumor development, but a hallmark of cancer cells that is required for anabolic processes. The dependencies of cancer cells on the altered metabolism may be exploited for new cancer treatments.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Levine AJ, Puzio-Kuter AM (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330(6009):1340–1344

    Article  PubMed  CAS  Google Scholar 

  2. Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    Article  PubMed  CAS  Google Scholar 

  3. Garber K (2006) Energy deregulation: licensing tumors to grow. Science 312(5777):1158–1159

    Article  PubMed  CAS  Google Scholar 

  4. Warburg O (1956) On respiratory impairment in cancer cells. Science 124(3215):269–270

    PubMed  CAS  Google Scholar 

  5. DeBerardinis RJ et al (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7(1):11–20

    Article  PubMed  CAS  Google Scholar 

  6. Weinhouse S (1956) On respiratory impairment in cancer cells. Science 124(3215):267–269

    Article  PubMed  CAS  Google Scholar 

  7. Chance B, Castor LN (1952) Some patterns of the respiratory pigments of ascites tumors of mice. Science 116(3008):200–202

    Article  PubMed  CAS  Google Scholar 

  8. Moreno-Sanchez R et al (2007) Energy metabolism in tumor cells. FEBS J 274(6):1393–1418

    Article  PubMed  CAS  Google Scholar 

  9. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899

    Article  PubMed  CAS  Google Scholar 

  10. Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441(7092):437–443

    Article  PubMed  CAS  Google Scholar 

  11. Pfeiffer T, Schuster S, Bonhoeffer S (2001) Cooperation and competition in the evolution of ATP-producing pathways. Science 292(5516):504–507

    Article  PubMed  CAS  Google Scholar 

  12. Curi R, Newsholme P, Newsholme EA (1988) Metabolism of pyruvate by isolated rat mesenteric lymphocytes, lymphocyte mitochondria and isolated mouse macrophages. Biochem J 250(2):383–388

    PubMed  CAS  Google Scholar 

  13. Swietach P, Vaughan-Jones RD, Harris AL (2007) Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev 26(2):299–310

    Article  PubMed  CAS  Google Scholar 

  14. Fischer K et al (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109(9):3812–3819

    Article  PubMed  CAS  Google Scholar 

  15. Sonveaux P et al (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118(12):3930–3942

    PubMed  CAS  Google Scholar 

  16. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033

    Article  PubMed  CAS  Google Scholar 

  17. Mazurek S et al (2005) Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol 15(4):300–308

    Article  PubMed  CAS  Google Scholar 

  18. Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achille’s heel. Cancer Cell 13(6):472–482

    Article  PubMed  CAS  Google Scholar 

  19. Jones RG, Thompson CB (2009) Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 23(5):537–548

    Article  PubMed  CAS  Google Scholar 

  20. Medes G, Thomas A, Weinhouse S (1953) Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res 13(1):27–29

    PubMed  CAS  Google Scholar 

  21. Fritz V, Fajas L (2010) Metabolism and proliferation share common regulatory pathways in cancer cells. Oncogene 29(31):4369–4377

    Article  PubMed  CAS  Google Scholar 

  22. Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7(10):763–777

    Article  PubMed  CAS  Google Scholar 

  23. Porstmann T et al (2009) A new player in the orchestra of cell growth: SREBP activity is regulated by mTORC1 and contributes to the regulation of cell and organ size. Biochem Soc Trans 37(Pt 1):278–283

    Article  PubMed  CAS  Google Scholar 

  24. Nadolski MJ, Linder ME (2007) Protein lipidation. FEBS J 274(20):5202–5210

    Article  PubMed  CAS  Google Scholar 

  25. Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11(5):325–337

    Article  PubMed  CAS  Google Scholar 

  26. Eagle H et al (1956) The growth response of mammalian cells in tissue culture to L-glutamine and L-glutamic acid. J Biol Chem 218(2):607–616

    PubMed  CAS  Google Scholar 

  27. Wise DR, Thompson CB (2010) Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 35(8):427–433

    Article  PubMed  CAS  Google Scholar 

  28. Locasale JW, Cantley LC (2010) Altered metabolism in cancer. BMC Biol 8:88

    Article  PubMed  Google Scholar 

  29. Yuneva M et al (2007) Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol 178(1):93–105

    Article  PubMed  CAS  Google Scholar 

  30. DeBerardinis RJ et al (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104(49):19345–19350

    Article  PubMed  CAS  Google Scholar 

  31. Forbes NS et al (2006) Estradiol stimulates the biosynthetic pathways of breast cancer cells: detection by metabolic flux analysis. Metab Eng 8(6):639–652

    Article  PubMed  CAS  Google Scholar 

  32. Kaelin WG Jr, Thompson CB (2010) Q&A: cancer: clues from cell metabolism. Nature 465(7298):562–564

    Article  PubMed  CAS  Google Scholar 

  33. Zhong H et al (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59(22):5830–5835

    PubMed  CAS  Google Scholar 

  34. Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2(1):38–47

    Article  PubMed  CAS  Google Scholar 

  35. Maxwell PH et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399(6733):271–275

    Article  PubMed  CAS  Google Scholar 

  36. Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20(1):51–56

    Article  PubMed  CAS  Google Scholar 

  37. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732

    Article  PubMed  CAS  Google Scholar 

  38. Macheda ML, Rogers S, Best JD (2005) Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 202(3):654–662

    Article  PubMed  CAS  Google Scholar 

  39. Semenza GL (2007) Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE 2007(407):cm8

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  41. Papandreou I et al (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3(3):187–197

    Article  PubMed  CAS  Google Scholar 

  42. Fukuda R et al (2007) HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129(1):111–122

    Article  PubMed  CAS  Google Scholar 

  43. Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29(5):625–634

    Article  PubMed  CAS  Google Scholar 

  44. Jiang BH et al (1997) V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res 57(23):5328–5335

    PubMed  CAS  Google Scholar 

  45. Dang CV, Le A, Gao P (2009) MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res 15(21):6479–6483

    Article  PubMed  CAS  Google Scholar 

  46. Gordan JD, Thompson CB, Simon MC (2007) HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12(2):108–113

    Article  PubMed  CAS  Google Scholar 

  47. Kim JW, Dang CV (2006) Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res 66(18):8927–8930

    Article  PubMed  CAS  Google Scholar 

  48. David CJ et al (2010) HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463(7279):364–368

    Article  PubMed  CAS  Google Scholar 

  49. Garber K (2004) Energy boost: the Warburg effect returns in a new theory of cancer. J Natl Cancer Inst 96(24):1805–1806

    Article  PubMed  Google Scholar 

  50. Nicklin P et al (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136(3):521–534

    Article  PubMed  CAS  Google Scholar 

  51. Gao P et al (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239):762–765

    Article  PubMed  CAS  Google Scholar 

  52. Li F et al (2005) Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25(14):6225–6234

    Article  PubMed  CAS  Google Scholar 

  53. Dang CV (1999) c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 19(1):1–11

    PubMed  CAS  Google Scholar 

  54. Coller HA et al (2000) Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc Natl Acad Sci USA 97(7):3260–3265

    Article  PubMed  CAS  Google Scholar 

  55. O’Connell BC et al (2003) A large scale genetic analysis of c-Myc-regulated gene expression patterns. J Biol Chem 278(14):12563–12573

    Article  PubMed  Google Scholar 

  56. Tennant DA, Duran RV, Gottlieb E (2010) Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10(4):267–277

    Article  PubMed  CAS  Google Scholar 

  57. Samuels Y et al (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7(6):561–573

    Article  PubMed  CAS  Google Scholar 

  58. Samuels Y et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554

    Article  PubMed  CAS  Google Scholar 

  59. Jia S et al (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454(7205):776–779

    PubMed  CAS  Google Scholar 

  60. Cairns P et al (1997) Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 57(22):4997–5000

    PubMed  CAS  Google Scholar 

  61. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274

    Article  PubMed  CAS  Google Scholar 

  62. Laughner E et al (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21(12):3995–4004

    Article  PubMed  CAS  Google Scholar 

  63. Pastorino JG, Hoek JB, Shulga N (2005) Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 65(22):10545–10554

    Article  PubMed  CAS  Google Scholar 

  64. Gogvadze V, Orrenius S, Zhivotovsky B (2008) Mitochondria in cancer cells: what is so special about them? Trends Cell Biol 18(4):165–173

    Article  PubMed  CAS  Google Scholar 

  65. Deberardinis RJ, Lum JJ, Thompson CB (2006) Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth. J Biol Chem 281(49):37372–37380

    Article  PubMed  CAS  Google Scholar 

  66. Porstmann T et al (2005) PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 24(43):6465–6481

    PubMed  CAS  Google Scholar 

  67. Gottesdiener KM et al (1988) Isolation and structural characterization of the human 4F2 heavy-chain gene, an inducible gene involved in T-lymphocyte activation. Mol Cell Biol 8(9):3809–3819

    PubMed  CAS  Google Scholar 

  68. Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E (2004) The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 64(7):2627–2633

    Article  PubMed  CAS  Google Scholar 

  69. Bensaad K et al (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126(1):107–120

    Article  PubMed  CAS  Google Scholar 

  70. Matoba S et al (2006) p53 regulates mitochondrial respiration. Science 312(5780):1650–1653

    Article  PubMed  CAS  Google Scholar 

  71. Hu W et al (2010) Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA 107(16):7455–7460

    Article  PubMed  CAS  Google Scholar 

  72. Budanov AV et al (2004) Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304(5670):596–600

    Article  PubMed  CAS  Google Scholar 

  73. Chen W et al (2009) Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response. Mol Cell 34(6):663–673

    Article  PubMed  CAS  Google Scholar 

  74. Teodoro JG et al (2006) p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase. Science 313(5789):968–971

    Article  PubMed  CAS  Google Scholar 

  75. Feng Z et al (2007) The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 67(7):3043–3053

    Article  PubMed  CAS  Google Scholar 

  76. Kawauchi K et al (2008) p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol 10(5):611–618

    Article  PubMed  CAS  Google Scholar 

  77. Blagosklonny MV et al (1998) p53 inhibits hypoxia-inducible factor-stimulated transcription. J Biol Chem 273(20):11995–11998

    Article  PubMed  CAS  Google Scholar 

  78. Baysal BE et al (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287(5454):848–851

    Article  PubMed  CAS  Google Scholar 

  79. Bayley JP, Devilee P (2010) Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree? Curr Opin Genet Dev 20(3):324–329

    Article  PubMed  CAS  Google Scholar 

  80. Hao HX et al (2009) SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325(5944):1139–1142

    Article  PubMed  CAS  Google Scholar 

  81. Tomlinson IP et al (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30(4):406–410

    Article  PubMed  CAS  Google Scholar 

  82. Parsons DW et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812

    Article  PubMed  CAS  Google Scholar 

  83. Yan H et al (2009) IDH1 and IDH2 mutations in gliomas. N Eng J Med 360(8):765–773

    Article  CAS  Google Scholar 

  84. Ward PS et al (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17(3):225–234

    Article  PubMed  CAS  Google Scholar 

  85. Kranendijk M et al (2010) IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330(6002):336

    Article  PubMed  CAS  Google Scholar 

  86. Dang L et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462(7274):739–744

    Article  PubMed  CAS  Google Scholar 

  87. Gross S et al (2010) Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 207(2):339–344

    Article  PubMed  CAS  Google Scholar 

  88. Vander Heiden MG (2011) Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10(9):671–684

    Article  PubMed  CAS  Google Scholar 

  89. Folger O et al (2011) Predicting selective drug targets in cancer through metabolic networks. Mol Syst Biol 7:501

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, National University of Singapore, Singapore, 117597, Singapore

    Angela M. Liu & Wei Wang

  2. Departments of Pharmacology and Surgery, National University of Singapore, Singapore, 117597, Singapore

    John M. Luk

  3. Department of Surgery, University of Hong Kong, Pokfulam, Hong Kong, China

    John M. Luk

  4. Institute of Molecular and Cell Biology, Biopolis, Singapore

    John M. Luk

Authors
  1. Angela M. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John M. Luk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John M. Luk .

Editor information

Editors and Affiliations

  1. Faculty of Medicine Building, Department of Surgery, University of Hong Kong, Sassoon Road 21, Hong Kong, Hong Kong SAR

    Nikki P. Lee

  2. Center for Biomedical Research, Population Council, York Ave. 1230, NEW YORK, 10021, New York, USA

    C.Y. Cheng

  3. Yong Loo Lin School of Medicine, Department of Pharmacology and Departmen, National University of Singapore, Medical Drive 10, Singapore, 117597, Singapore

    John M. Luk

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Liu, A.M., Wang, W., Luk, J.M. (2013). Targeting Cancer Metabolisms. In: Lee, N., Cheng, C., Luk, J. (eds) New Advances on Disease Biomarkers and Molecular Targets in Biomedicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-456-2_9

Download citation

Publish with us

Policies and ethics

Search

Navigation