Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen

Abstract

As a new faculty member at The Johns Hopkins University, School of Medicine, the author began research on cancer in 1969 because this frequently fatal disease touched many whom he knew. He was intrigued with its viscous nature, the failure of all who studied it to find a cure, and also fascinated by the pioneering work of Otto Warburg, a biochemical legend and Nobel laureate. Warburg who died 1 year later in 1970 had shown in the 1920s that the most striking biochemical phenotype of cancers is their aberrant energy metabolism. Unlike normal tissues that derive most of their energy (ATP) by metabolizing the sugar glucose to carbon dioxide and water, a process that involves oxygen-dependent organelles called “mitochondria”, Warburg showed that cancers frequently rely less on mitochondria and obtain as much as 50% of their ATP by metabolizing glucose directly to lactic acid, even in the presence of oxygen. This frequent phenotype of cancers became known as the “Warburg effect”, and the author of this review strongly believed its understanding would facilitate the discovery of a cure. Following in the final footsteps of Warburg and caught in the midst of an unpleasant anti-Warburg, anti-metabolic era, the author and his students/collaborators began quietly to identify the key molecular events involved in the “Warburg effect”. Here, the author describes via a series of sequential discoveries touching five decades how despite some impairment in the respiratory capacity of malignant tumors, that hexokinase 2 (HK-2), its mitochondrial receptor (VDAC), and the gene that encodes HK-2 (HK-2 gene) play the most pivotal and direct roles in the “Warburg effect”. They discovered also that like a “Trojan horse” the simple lactic acid analog 3-bromopyruvate selectively enters the cells of cancerous animal tumors that exhibit the “Warburg effect” and quickly dissipates their energy (ATP) production factories (i.e., glycolysis and mitochondria) resulting in tumor destruction without harm to the animals.

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References

  1. Ahmed FE (2007) J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 25:101–154

    CAS  Google Scholar 

  2. Altenberg B, Greulich KO (2004) Genomics 84:1014–1020

    Article  CAS  Google Scholar 

  3. Arora KK, Pedersen PL (1988) J Biol Chem 263:17422–17428

    CAS  Google Scholar 

  4. Arora KK, Fanciulli M, Pederson PL (1990) J Biol Chem 265:6481–6488

    CAS  Google Scholar 

  5. Arora KK, Filburn CR, Pederson PL (1991) J Biol Chem 266:5359–5362

    CAS  Google Scholar 

  6. Arora KK, Filburn CR, Pederson PL (1993) J Biol Chem 268:18259–18266

    CAS  Google Scholar 

  7. Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V (2004) Biochem J 377(Pt 2):347–355

    Article  CAS  Google Scholar 

  8. Bennett WS Jr., Steitz TA (1980) J Mol Biol 140:183–209

    Article  CAS  Google Scholar 

  9. Birnbaum MJ (2004) Dev Cell 7:781–782

    Article  CAS  Google Scholar 

  10. Bustamante E, Pedersen PL (1977) Proc Natl Acad Sci USA 74:3735–3739

    Article  CAS  Google Scholar 

  11. Bustamante E, Morris HP, Pedersen PL (1981) J Biol Chem 256:8699–8704

    CAS  Google Scholar 

  12. Burk D, Woods M, Hunter J (1967) J Natl Cancer Inst 38:839–863

    CAS  Google Scholar 

  13. Chan TL, Greenawalt, JW, Pedersen PL (1970) J Cell Biol 45:291–305

    Article  CAS  Google Scholar 

  14. Chen C, Ko YH, Delannoy M, Ludtke SJ, Chiu W, Pedersen PL (2004) 279:31761–31768

  15. Chen C, Saxena AK, Simcoke WN, Garboczi DN, Pedersen PL, Ko YH (2006) J Biol Chem 281:13777–13783

    Article  CAS  Google Scholar 

  16. Colombini M (1979) Nature 279:643–645

    Article  CAS  Google Scholar 

  17. Devlin TM (2006) Textbook of Biochemistry with Clinical Correlations (6th edition): Chapter 15: Harris RA Carbohydrate Metabolism I: Major metabolic pathways and their controls pp 582–608

  18. Di Chiro G, DeLaPaz RL, Brooks RA, Sokoloff L, Kornblith PL, Smith BH, Patronas NJ, Kufta CV, Kessler RM, Johnston GS, Manning RG, Wolf AP (1982) Neurology 32:1323–1329

    Google Scholar 

  19. Emboli ML, Paradies G, Galeotti T, Papa S (1977) Biochim Biophys Acta 460:183–187

    Article  Google Scholar 

  20. Galluzzi L, Larochette N, Zamazami N, Kroemer G (2006) Oncogene 25:4812–4830

    Article  CAS  Google Scholar 

  21. Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL (2002) Cancer Res 62:3909–3913

    CAS  Google Scholar 

  22. Goel A, Mathupala SP, Pedersen PL (2003) J Biol Chem 278:15333–15340

    Article  CAS  Google Scholar 

  23. Hammerman PS, Fox CJ, Thompson, CB (2004) Trends Biochem Sci 29:586–592

    Article  CAS  Google Scholar 

  24. Herceg Z (2007) Mutagenesis 22:91–103

    Article  CAS  Google Scholar 

  25. Indo T, Wan CN, Casella V et al (1978) J Label Compds Radiopharm 24:174–183

    Google Scholar 

  26. Kelloff GJ, Hoffman JM, Johnson B, Scher HI, Siegel BA, Cheng EY, Cheson BD, O’shaughnessy J, Guyton KZ, Mankoff DA, Shankar L, Larson SM, Sigman CC, Schilsky RL, Sullivan DC (2005) Clin Cancer Res 11:2785–2808

    Article  CAS  Google Scholar 

  27. Kim JW, Dang CV (2006) Cancer Res 66:8927–8930

    Article  CAS  Google Scholar 

  28. Ko YH, McFadden BA (1990) Arch Biochem Biophys 278:373–380

    Article  CAS  Google Scholar 

  29. Ko YH, Pedersen PL, Geschwind JF (2001) Cancer Lett 173:83–91

    Article  CAS  Google Scholar 

  30. Ko YH, Delannoy M, Hullihen J, Chiu W, Pedersen PL (2003) J Biol Chem 278:12305–12309

    Article  CAS  Google Scholar 

  31. Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL (2004) Biochem Biophys Res Commun 324:269–275

    Article  CAS  Google Scholar 

  32. Lee MG, Pedersen PL (2003) J Biol Chem 278:41047–41058

    Article  CAS  Google Scholar 

  33. Lemasters JJ, Holmuhamedov E (2006) Biochim Biophys Acta 1762:181–190

    CAS  Google Scholar 

  34. Linden M, Gellerfors P, Nelson BD (1982) FEBS Lett 141:189–192

    Article  CAS  Google Scholar 

  35. Lo CH, Farina F, Morris HP, Weinhouse S (1968) Adv Enzyme Regul 6:453–464

    Article  CAS  Google Scholar 

  36. Mathupala SP, Pedersen PL (1999) Proc Amer Assoc Cancer Res (Philadelphia, PA) Abs. #145, 22

  37. Mathupala SP, Rempel A, Pedersen PL (1995) J Biol Chem 270:16918–16925

    Article  CAS  Google Scholar 

  38. Mathupala SP, Heese C, Pedersen PL (1997) J Biol Chem 272:22776–22780

    Article  CAS  Google Scholar 

  39. Mathupala SP, Rempel A, Pedersen PL (2001) J Biol Chem 276:43407–43412

    Article  CAS  Google Scholar 

  40. Mathupala SP, Ko YH, Pedersen PL (2006) Oncogene 25:4777–4786

    Article  CAS  Google Scholar 

  41. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Hay N (2004a) Mol Cell 16:819–830

    Article  CAS  Google Scholar 

  42. Majewski N, Nogueira V, Robey RB, Hay N (2004b) Mol Cell Biol 24:730–740

    Article  CAS  Google Scholar 

  43. Merida I, Avila-Flores A (2006) Clin Transl Oncol 8:711–716

    Article  CAS  Google Scholar 

  44. Modica-Napolitano JS, Kulawiec M, Singh KK (2007) Curr Mol Med 7:121–131

    Article  CAS  Google Scholar 

  45. Morris HP (1965) Adv Cancer Res 9:227–302

    CAS  Article  Google Scholar 

  46. Nakashima RA, Mangan PS, Colombini M, Pedersen PL (1986) Biochemistry 25:1015–10121

    Article  CAS  Google Scholar 

  47. Nakashima RA, Paggi MC, Scott LJ, Pedersen PL (1988) Cancer Res 48:913–919

    CAS  Google Scholar 

  48. Nelson BD, Kabir F, Muchiri P (1984) Biochem J 219:159–164

    CAS  Google Scholar 

  49. Pedersen PL (1978) Prog Exp Tumor Res 22:190–274

    CAS  Google Scholar 

  50. Pedersen PL (2007) J Bioenerg Biomemb 39:1–12

    Article  CAS  Google Scholar 

  51. Pedersen PL, Greenawalt JW, Chan TL, Morris HP (1970) Cancer Res 30:2620–2626

    CAS  Google Scholar 

  52. Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH (2002) Biochem Biophys Acta 1555:14–20

    Article  CAS  Google Scholar 

  53. Parry D, Pedersen PL (1983) J Biol Chem 258:10904–10912

    CAS  Google Scholar 

  54. Pastorino JG, Hoek JB (2003) Curr Med Chem 10:1535–1551

    Article  CAS  Google Scholar 

  55. Pastorino JG, Shulga N, Hoek JB (2002) J Biol Chem 277:7610–7618

    Article  CAS  Google Scholar 

  56. Pauser S, Wagner S, Lippmann M, Pohlen U, Reszka R, Wolf KJ, Berger G (1996) Cancer Res 56:1863–1867

    CAS  Google Scholar 

  57. Phelps ME (2000) Proc Natl Acad Sci 97:9226–9233

    Article  CAS  Google Scholar 

  58. Phelps ME, Hoffman EF, Mullani NA, Ter-Pogossian MM (1975) In: Deblanc H, Sorenson JA (eds) Non-invasive brain imaging, radionuclides and computed tomography. New York: Soc Nucl Med 87–109 Rose IA, Warms JV (1967) J Biol Chem 242:1635–1645

  59. Rempel A, Mathupala SP, Griffin CA, Hawkins AL, Pedersen PL (1996) Cancer Res 56:2468–2471

    CAS  Google Scholar 

  60. Ristow M (2006) Curr Opin Clin Nutr Metab Care 9:339–345

    CAS  Article  Google Scholar 

  61. Robey RB, Hay N (2005) Cell Cycle 4:654–658

    CAS  Google Scholar 

  62. Robey RB, Hay N (2006) Oncogene 25:4683–4696

    Article  CAS  Google Scholar 

  63. Rose IA, Warms JV (1967) J Biol Chem 242:1635–1645

    CAS  Google Scholar 

  64. Rostovtseva TK, Tan W, Colombini M (2005) J Bioenerg Biomemb 37:129–142

    Article  CAS  Google Scholar 

  65. Schnaitman C, Greenawalt JW (1968) J Cell Biol 38:158–175

    Article  CAS  Google Scholar 

  66. Schreiber JR, Balcavage WX, Morris HP, Pedersen PL (1970) Cancer Res 30:2497–2501

    CAS  Google Scholar 

  67. Smith DF, Walborg EF Jr, Chang JP (1970) Cancer Res 30:2306–2309

    CAS  Google Scholar 

  68. Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB (2001) Mol Cell Bio 21:5899–5912

    Article  CAS  Google Scholar 

  69. Wallace DC (2005) Cold Spring Harb Symp Quant Biol 70:363–374

    Article  CAS  Google Scholar 

  70. Warburg O (1930) The metabolism of tumours. London Constable Co Ltd, 1930

  71. Warburg O (1956) Science 124:269–270

    CAS  Google Scholar 

  72. Weber G, Lea MA (1966) Adv Enzyme Regul 4:115–145

    Article  CAS  Google Scholar 

  73. Zaid H, Abu-Hamad S, Israelson A, Nathan I, Shoshan-Barmatz V (2005) Cell Death Differ 12:751–760

    Article  CAS  Google Scholar 

Download references

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Correspondence to Peter L. Pedersen.

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Pedersen, P.L. Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr 39, 211 (2007). https://doi.org/10.1007/s10863-007-9094-x

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Keywords

  • Cancer
  • “Warburg effect”
  • Glycolysis
  • Mitochondria
  • Hexokinase 2
  • Drug target
  • Cancer therapy
  • 3-bromopyruvate
  • Positron emission tomography (PET)