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

Introduction

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.

Keywords

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

References

  1. Ahmed FE (2007) J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 25:101–154Google Scholar
  2. Altenberg B, Greulich KO (2004) Genomics 84:1014–1020CrossRefGoogle Scholar
  3. Arora KK, Pedersen PL (1988) J Biol Chem 263:17422–17428Google Scholar
  4. Arora KK, Fanciulli M, Pederson PL (1990) J Biol Chem 265:6481–6488Google Scholar
  5. Arora KK, Filburn CR, Pederson PL (1991) J Biol Chem 266:5359–5362Google Scholar
  6. Arora KK, Filburn CR, Pederson PL (1993) J Biol Chem 268:18259–18266Google Scholar
  7. Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V (2004) Biochem J 377(Pt 2):347–355CrossRefGoogle Scholar
  8. Bennett WS Jr., Steitz TA (1980) J Mol Biol 140:183–209CrossRefGoogle Scholar
  9. Birnbaum MJ (2004) Dev Cell 7:781–782CrossRefGoogle Scholar
  10. Bustamante E, Pedersen PL (1977) Proc Natl Acad Sci USA 74:3735–3739CrossRefGoogle Scholar
  11. Bustamante E, Morris HP, Pedersen PL (1981) J Biol Chem 256:8699–8704Google Scholar
  12. Burk D, Woods M, Hunter J (1967) J Natl Cancer Inst 38:839–863Google Scholar
  13. Chan TL, Greenawalt, JW, Pedersen PL (1970) J Cell Biol 45:291–305CrossRefGoogle Scholar
  14. Chen C, Ko YH, Delannoy M, Ludtke SJ, Chiu W, Pedersen PL (2004) 279:31761–31768Google Scholar
  15. Chen C, Saxena AK, Simcoke WN, Garboczi DN, Pedersen PL, Ko YH (2006) J Biol Chem 281:13777–13783CrossRefGoogle Scholar
  16. Colombini M (1979) Nature 279:643–645CrossRefGoogle 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 582–608Google Scholar
  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 32:1323–1329Google Scholar
  19. Emboli ML, Paradies G, Galeotti T, Papa S (1977) Biochim Biophys Acta 460:183–187CrossRefGoogle Scholar
  20. Galluzzi L, Larochette N, Zamazami N, Kroemer G (2006) Oncogene 25:4812–4830CrossRefGoogle Scholar
  21. Geschwind JF, Ko YH, Torbenson MS, Magee C, Pedersen PL (2002) Cancer Res 62:3909–3913Google Scholar
  22. Goel A, Mathupala SP, Pedersen PL (2003) J Biol Chem 278:15333–15340CrossRefGoogle Scholar
  23. Hammerman PS, Fox CJ, Thompson, CB (2004) Trends Biochem Sci 29:586–592CrossRefGoogle Scholar
  24. Herceg Z (2007) Mutagenesis 22:91–103CrossRefGoogle Scholar
  25. Indo T, Wan CN, Casella V et al (1978) J Label Compds Radiopharm 24:174–183Google 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 11:2785–2808CrossRefGoogle Scholar
  27. Kim JW, Dang CV (2006) Cancer Res 66:8927–8930CrossRefGoogle Scholar
  28. Ko YH, McFadden BA (1990) Arch Biochem Biophys 278:373–380CrossRefGoogle Scholar
  29. Ko YH, Pedersen PL, Geschwind JF (2001) Cancer Lett 173:83–91CrossRefGoogle Scholar
  30. Ko YH, Delannoy M, Hullihen J, Chiu W, Pedersen PL (2003) J Biol Chem 278:12305–12309CrossRefGoogle Scholar
  31. Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL (2004) Biochem Biophys Res Commun 324:269–275CrossRefGoogle Scholar
  32. Lee MG, Pedersen PL (2003) J Biol Chem 278:41047–41058CrossRefGoogle Scholar
  33. Lemasters JJ, Holmuhamedov E (2006) Biochim Biophys Acta 1762:181–190Google Scholar
  34. Linden M, Gellerfors P, Nelson BD (1982) FEBS Lett 141:189–192CrossRefGoogle Scholar
  35. Lo CH, Farina F, Morris HP, Weinhouse S (1968) Adv Enzyme Regul 6:453–464CrossRefGoogle Scholar
  36. Mathupala SP, Pedersen PL (1999) Proc Amer Assoc Cancer Res (Philadelphia, PA) Abs. #145, 22Google Scholar
  37. Mathupala SP, Rempel A, Pedersen PL (1995) J Biol Chem 270:16918–16925CrossRefGoogle Scholar
  38. Mathupala SP, Heese C, Pedersen PL (1997) J Biol Chem 272:22776–22780CrossRefGoogle Scholar
  39. Mathupala SP, Rempel A, Pedersen PL (2001) J Biol Chem 276:43407–43412CrossRefGoogle Scholar
  40. Mathupala SP, Ko YH, Pedersen PL (2006) Oncogene 25:4777–4786CrossRefGoogle Scholar
  41. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Hay N (2004a) Mol Cell 16:819–830CrossRefGoogle Scholar
  42. Majewski N, Nogueira V, Robey RB, Hay N (2004b) Mol Cell Biol 24:730–740CrossRefGoogle Scholar
  43. Merida I, Avila-Flores A (2006) Clin Transl Oncol 8:711–716CrossRefGoogle Scholar
  44. Modica-Napolitano JS, Kulawiec M, Singh KK (2007) Curr Mol Med 7:121–131CrossRefGoogle Scholar
  45. Morris HP (1965) Adv Cancer Res 9:227–302CrossRefGoogle Scholar
  46. Nakashima RA, Mangan PS, Colombini M, Pedersen PL (1986) Biochemistry 25:1015–10121CrossRefGoogle Scholar
  47. Nakashima RA, Paggi MC, Scott LJ, Pedersen PL (1988) Cancer Res 48:913–919Google Scholar
  48. Nelson BD, Kabir F, Muchiri P (1984) Biochem J 219:159–164Google Scholar
  49. Pedersen PL (1978) Prog Exp Tumor Res 22:190–274Google Scholar
  50. Pedersen PL (2007) J Bioenerg Biomemb 39:1–12CrossRefGoogle Scholar
  51. Pedersen PL, Greenawalt JW, Chan TL, Morris HP (1970) Cancer Res 30:2620–2626Google Scholar
  52. Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH (2002) Biochem Biophys Acta 1555:14–20CrossRefGoogle Scholar
  53. Parry D, Pedersen PL (1983) J Biol Chem 258:10904–10912Google Scholar
  54. Pastorino JG, Hoek JB (2003) Curr Med Chem 10:1535–1551CrossRefGoogle Scholar
  55. Pastorino JG, Shulga N, Hoek JB (2002) J Biol Chem 277:7610–7618CrossRefGoogle Scholar
  56. Pauser S, Wagner S, Lippmann M, Pohlen U, Reszka R, Wolf KJ, Berger G (1996) Cancer Res 56:1863–1867Google Scholar
  57. Phelps ME (2000) Proc Natl Acad Sci 97:9226–9233CrossRefGoogle 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 242:1635–1645Google Scholar
  59. Rempel A, Mathupala SP, Griffin CA, Hawkins AL, Pedersen PL (1996) Cancer Res 56:2468–2471Google Scholar
  60. Ristow M (2006) Curr Opin Clin Nutr Metab Care 9:339–345CrossRefGoogle Scholar
  61. Robey RB, Hay N (2005) Cell Cycle 4:654–658Google Scholar
  62. Robey RB, Hay N (2006) Oncogene 25:4683–4696CrossRefGoogle Scholar
  63. Rose IA, Warms JV (1967) J Biol Chem 242:1635–1645Google Scholar
  64. Rostovtseva TK, Tan W, Colombini M (2005) J Bioenerg Biomemb 37:129–142CrossRefGoogle Scholar
  65. Schnaitman C, Greenawalt JW (1968) J Cell Biol 38:158–175CrossRefGoogle Scholar
  66. Schreiber JR, Balcavage WX, Morris HP, Pedersen PL (1970) Cancer Res 30:2497–2501Google Scholar
  67. Smith DF, Walborg EF Jr, Chang JP (1970) Cancer Res 30:2306–2309Google Scholar
  68. Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB (2001) Mol Cell Bio 21:5899–5912CrossRefGoogle Scholar
  69. Wallace DC (2005) Cold Spring Harb Symp Quant Biol 70:363–374CrossRefGoogle Scholar
  70. Warburg O (1930) The metabolism of tumours. London Constable Co Ltd, 1930Google Scholar
  71. Warburg O (1956) Science 124:269–270Google Scholar
  72. Weber G, Lea MA (1966) Adv Enzyme Regul 4:115–145CrossRefGoogle Scholar
  73. Zaid H, Abu-Hamad S, Israelson A, Nathan I, Shoshan-Barmatz V (2005) Cell Death Differ 12:751–760CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Biological ChemistryJohns Hopkins University, School of MedicineBaltimoreUSA

Personalised recommendations