Skip to main content
SpringerLink
Log in

Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Cancer cells have been shown to have altered metabolism when compared to normal non-malignant cells. The Warburg effect describes a phenomenon in which cancer cells preferentially metabolize glucose by glycolysis, producing lactate as an end product, despite being the presence of oxygen. The phenomenon was first described by Otto Warburg in the 1920s, and has resurfaced as a controversial theory, with both supportive and opposing arguments. The biochemical aspects of the Warburg effect outline a strong explanation for the cause of cancer cell proliferation, by providing the biological requirements for a cell to grow. Studies have shown that pathways such as phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) as well as hypoxia inducible factor-1 (HIF-1) are central regulators of glycolysis, cancer metabolism and cancer cell proliferation. Studies have shown that PI3K signaling pathways have a role in many cellular processes such as metabolism, inflammation, cell survival, motility and cancer progression. Herein, the cellular aspects of the PI3K pathway are described, as well as the influence HIF has on cancer cell metabolism. HIF-1 activation has been related to angiogenesis, erythropoiesis and modulation of key enzymes involved in aerobic glycolysis, thereby modulating key processes required for the Warburg effect. In this review we discuss the molecular aspects of the Warburg effect with a particular emphasis on the role of the HIF-1 and the PI3K pathway.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Registries A.I.o.H.a.W.A.A.o.C. (2012) Cancer in Australia: an overview. AIHW, Canberra

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

    Article  Google Scholar 

  3. 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  CAS  PubMed  Google Scholar 

  4. Seyfried T, Shelton L (2010) Cancer as a metabolic disease. Nutr Metab 7(1):7

    Article  Google Scholar 

  5. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  CAS  PubMed  Google Scholar 

  6. Morton JS (1980) Glycolysis and alcoholic fermentation. Acts Facts 9:12

    Google Scholar 

  7. López-Lázaro M (2008) The Warburg effect: why and how do cancer cells activate glycolysis in the presence of oxygen? Anti-Cancer Agents Med Chem 8(3):305–312

    Article  Google Scholar 

  8. Tisdale MJ (2009) Mechanisms of cancer cachexia. Physiol Rev 89:381–410

    Article  CAS  PubMed  Google Scholar 

  9. Stephenson L (2013) Cancer metabolism. Biofiles 7(4):5–12

  10. Dang CV (2010) Rethinking the Warburg effect with Myc micromanagin glutamine metabolism. Cancer Res 70:859

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Weinhouse S (1976) The Warburg hypothesis fifty years later. Zeitschrift für Krebsforschung und Klinische. Onkologie 87(2):115–126

    CAS  Google Scholar 

  12. Seyfried N, Shelton LM (2010) Cancer as a metabolic disease. Nutr Metab 7(7):1–22

    Google Scholar 

  13. Singh KK, Kulawiec M, Still I, Desouki MM, Geradts J, Matsui S (2005) Intergenomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis. Gene 354:140–146

    Article  CAS  PubMed  Google Scholar 

  14. Petros JA, Baumann A, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, Lim S, Issa MM, Flanders WD, Hosseini SH, Marshall FF, Wallace DC (2005) mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA 102:719–724

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Bertram JS (2000) The molecular biology of cancer. Mol Aspects Med 21(6):167–223

    Article  CAS  PubMed  Google Scholar 

  16. Warburg O (1966) The prime cause and prevention of cancer. In: Meeting of the nobel-laureates. Lake Constance, Lindau

  17. Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134(5):703–707

    Article  CAS  PubMed  Google Scholar 

  18. Martini M, De Santis MC, Braccin L, Gulluni F, Hirsch E (2014) PI3K/AKT signalling pathway and cancer: an updated review. Ann Med 46(6):372–383

    Article  CAS  PubMed  Google Scholar 

  19. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11:329–341

    Article  CAS  PubMed  Google Scholar 

  20. DeBerardinis RJ et al (2007) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7(1):11–20

    Article  Google Scholar 

  21. Vara JÁF et al (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30(2):193–204

    Article  CAS  Google Scholar 

  22. Simons AL, Orcutt KP, Madsen JM, Spitz DR, Scarbrough PM (2012) The role of Akt pathway signaling in glucose metabolism and metabolic oxidative stress. Oxidative Stress in Applied Basic Research and Clinical Practice, pp 21–48

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. O’Neill Abraham AG (2010) PI3K/Akt-mediated regulation of p53 in cancer. Biochem Soc Trans 42(4):798–803

    Google Scholar 

  25. Zhivotovsky B, Orrenius S (2009) The Warburg effect returns to the cancer stage. Semin Cancer Biol 19(1):1–3

    Article  PubMed  Google Scholar 

  26. Semenza GL (2011) Hypoxia-inducible factor. 1 Regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochimica et Biophysica Acta 1813(7):1263–1268

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Activation of the HIF pathway in cancer. Curr Opin Genet Dev 11(3):293–299

    Article  CAS  PubMed  Google Scholar 

  28. Loboda A, Litwin JA, Dulak J (2010) HIF-1 and HIF-2 transcription factors—similar but not identical. Mol Cells 29:435–442

    Article  CAS  PubMed  Google Scholar 

  29. Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15(20):2675–2686

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Solaini G et al (2010) Hypoxia and mitochondrial oxidative metabolism. Biochimica et Biophysica Acta 1797(6):1171–1177

    Article  CAS  PubMed  Google Scholar 

  31. Semenza GL (2009) Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol 19(1):12–16

    Article  CAS  PubMed  Google Scholar 

  32. Lu H, Forbes RA, Verma A (2002) R.A.F.a.A.V., Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277:23111–23115

    Article  CAS  PubMed  Google Scholar 

  33. Semenza G (2007) HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 39:231–234

    Article  CAS  PubMed  Google Scholar 

  34. Manalo DJ et al (2005) Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105(2):659–669

    Article  CAS  PubMed  Google Scholar 

  35. Minet E et al (2000) Role of HIF-1 as a transcription factor involved in embryonic development, cancer progression and apoptosis (review). Int J Mol Med 5(3):253–262

    CAS  PubMed  Google Scholar 

  36. 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 

  37. Simon CM (2006) HIF-1 and mitochondrial oxygen consumption. Cell Metab 3(3):150–151

    Article  CAS  PubMed  Google Scholar 

  38. Cavadas MAS, Nguyen LK, Cheong A (2013) Hypoxia-inducible factor (HIF) network: insights from mathematical models. Cell Commun Signal 11(42):1–16

    Google Scholar 

  39. Weljie AM, Jirik FR (2011) Hypoxia-induced metabolic shifts in cancer cells: moving beyond the Warburg effect. Int J Biochem Cell Biol 43(7):981–989

    Article  CAS  PubMed  Google Scholar 

  40. Brahimi-Horn MC, Chiche J, Pouysségur J (2007) Hypoxia signalling controls metabolic demand. Curr Opin Cell Biol 19(2):223–229

    Article  CAS  PubMed  Google Scholar 

  41. Bergeron M et al (2000) Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol 48(3):285–296

    Article  CAS  PubMed  Google Scholar 

  42. Lu H, Forbes RA, Verma A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277(26):23111–23115

    Article  CAS  PubMed  Google Scholar 

  43. Ciuffreda L et al (2014) PTEN expression and function in adult cancer stem cells and prospects for therapeutic targeting. Adv Biol Regul 56:66–80

    Article  CAS  PubMed  Google Scholar 

  44. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT (2002) Regulation of hypoxia-inducible factor 1 alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22(20):7004–7014

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. He M et al (2013) HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation. Cell Death Differ 20(3):408–418

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Adekola K, Rosen ST, Shanmugam M (2012) Glucose transporters in cancer metabolism. Curr Opin Oncol 24(6):650–654

    Article  CAS  PubMed  Google Scholar 

  47. Chen JQ, Russo J (2012) Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta 1826(2):370–384

    CAS  PubMed  Google Scholar 

  48. Ren BF et al (2008) Hypoxia regulation of facilitated glucose transporter-1 and glucose transporter-3 in mouse chondrocytes mediated by HIF-1a. Joint Bone Spine 75(2):176–181

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Ma N (2010) HIF-1 is the commander of gateways to cancer. J Cancer Sci Ther 3:35–40

    Google Scholar 

  51. Wu CH et al (2009) In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter. Int J Cancer 124(9):2210–2219

    Article  CAS  PubMed  Google Scholar 

  52. DellAntone P (2009) Targets of 3-bromopyruvate, a new, energy depleting, anticancer agent. Med Chem 5(6):491–496

    Article  CAS  Google Scholar 

  53. Luo W, Semenza GL (2011) Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget 2(7):551–556

    PubMed Central  PubMed  Google Scholar 

  54. Luo W et al (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145(5):732–744

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Christofk HR et al (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452(7184):230–233

    Article  CAS  PubMed  Google Scholar 

  56. Koukourakis MI et al (2006) Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway—a report of the Tumour Angiogenesis Research Group. J Clin Oncol 24(26):4301–4308

    Article  CAS  PubMed  Google Scholar 

  57. Halestrap AP, Wilson MCW (2012) The monocarboxylate transporter family—role and regulation. Life 64(2):109–119

    CAS  PubMed  Google Scholar 

  58. Sonveaux P et al (2012) Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS ONE 7(3):13

    Article  Google Scholar 

  59. Cori CF, Cori GT (1929) Glycogen formation in the liver from d-and l-lactic acid. J Biol Chem 81(2):389–403

    CAS  Google Scholar 

  60. Holness M, Sugden M (2003) Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem Soc Trans 31(6):1143–1151

    Article  CAS  PubMed  Google Scholar 

  61. Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99(7):989–994

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Bonnet S et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11(1):37–51

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

TCK is supported by an Australian Research Council Future Fellowship and the Epigenomic Medicine Laboratory is supported by McCord Research. 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, VIC, Australia

    Rupert Courtnay, Darleen C. Ngo, Neha Malik, Katherine Ververis & Tom C. Karagiannis

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

    Rupert Courtnay, Darleen C. Ngo, Neha Malik, Katherine Ververis & Tom C. Karagiannis

  3. Department of Agriculture and Food Systems, Melbourne School of Land and Environment, The University of Melbourne, Parkville, VIC, Australia

    Stephanie M. Tortorella

  4. Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, VIC, Australia

    Stephanie M. Tortorella

Authors
  1. Rupert Courtnay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darleen C. Ngo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Neha Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Katherine Ververis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephanie M. Tortorella
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tom C. Karagiannis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tom C. Karagiannis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Courtnay, R., Ngo, D.C., Malik, N. et al. Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep 42, 841–851 (2015). https://doi.org/10.1007/s11033-015-3858-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-015-3858-x

Keywords

Search

Navigation