Reprogramming of Cancer Cell Metabolism: Warburg and Reverse Warburg Hypothesis

  • Samyukta Narayanan
  • Anirudh Santhoshkumar
  • Srijit Ray
  • Sitaram Harihar


Every cell requires energy which they obtain from oxidative phosphorylation to perform major metabolic functions. This energy requirement is dependent on their metabolic rate, and it is expected that higher the metabolic rate, higher is the amount of energy expended. However, cancer cells have a unique metabolic behavior where they require only a minimal amount of energy, exhibiting a condition called the Warburg effect to survive and proliferate. They undergo glycolysis despite the availability of adequate oxygen (aerobic glycolysis) and obtain less energy as compared to normal cells from this process. This finding has helped many researchers to look for an alternative in treating cancer which is one of the leading causes of death today. This chapter will elucidate on the role of Warburg effect in modulating cancer cell metabolism and describe recent findings on this unique pathway employed by cancer cells. The chapter will also shed light on an alternative model called the reverse Warburg effect that provides an environment rich in energy for tumor growth and discuss the potential of using this pathway for therapeutically targeting cancer cells.


Cancer Metastasis Metabolism Glycolysis Warburg effect Microenvironment Oxidative phosphorylation 



The authors would like to thank Keerthika J. Jayachandran for helping them with the graphic design of Fig. 2.1.

Financial support: S.H. laboratory is supported by selective excellence initiative grant from the SRM Institute of Science and Technology.


  1. Abdel-Haleem AM, Lewis NE, Jamshidi N, Mineta K, Gao X, Gojobori T (2017) The emerging facets of non-cancerous Warburg effect. Front Endocrinol 8:1–7. Scholar
  2. Adekola K, Rosen ST, Shanmugam M (2012) Glucose transporters in cancer metabolism. Curr Opin Oncol 24:650–654. Scholar
  3. Barron CC, Bilan PJ, Tsakiridis T, Tsiani E (2016) Facilitative glucose transporters: implications for cancer detection, prognosis and treatment. Metabolism 65:124–139. Scholar
  4. Bonuccelli G, Whitaker-Menezes D, Castello-Cros R, Pavlides S, Pestell RG, Fatatis A, Witkiewicz AK, Vander Heiden MG, Migneco G, Chiavarina B, Frank PG, Capozza F, Flomenberg N, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2010) The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts. Cell Cycle 9:1960–1971. Scholar
  5. Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC (2015) Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep 42:841–851. Scholar
  6. Dang CV (2010) Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res 70:859–863. Scholar
  7. Danhier P, Ba P, Payen VL, Grasso D, Ippolito L, Sonveaux P, Porporato PE (2017) Cancer metabolism in space and time: beyond the Warburg effect. Biochim Biophys Acta 1858:556–572. Scholar
  8. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64:3892–3899. Scholar
  9. Fadaka A, Ajiboye B, Ojo O, Adewale O, Olayide I, Emuowhochere R (2017) Biology of glucose metabolization in cancer cells. J Oncol Sci 3:45–51. Scholar
  10. Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B, Mamer OA, Avizonis D, Deberardinis RJ, Siegel PM, Jones RG (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17:113–124. Scholar
  11. Feng Y, Liu J, Guo W, Guan Y, Xu H, Guo Q, Song X, Yi F, Liu T, Zhang W, Dong X, Cao LL, O’Rourke BP, Cao LL (2018) Atg7 inhibits Warburg effect by suppressing PKM2 phosphorylation resulting reduced epithelial-mesenchymal transition. Int J Biol Sci 14:755–783. Scholar
  12. Finley LWS, Carracedo A, Lee J, Souza A, Egia A, Zhang J, Teruya-Feldstein J, Moreira PI, Cardoso SM, Clish CB, Pandolfi PP, Haigis MC (2011) SIRT3 opposes reprogramming of cancer cell metabolism through HIF1$α$ destabilization. Cancer Cell 19:416–428. Scholar
  13. Fu Y, Liu S, Yin S, Niu W, Xiong W, Tan M, Li G, Zhou M (2017) The reverse Warburg effect is likely to be an Achilles’ heel of cancer that can be exploited for cancer therapy. Oncotarget 8:57813–57825. Scholar
  14. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899. Scholar
  15. Gonzalez CD, Alvarez S, Ropolo A, Rosenzvit C, Gonzalez Bagnes MF, Vaccaro MI (2014) Autophagy, Warburg, and Warburg reverse effects in human cancer. Biomed Res Int 2014:1–10. Scholar
  16. Gottlieb E, Tomlinson IPM (2005) Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5:857–866. Scholar
  17. Hitosugi T, Kang S, Heiden MGV, Chung T-w, Elf S, Lythgoe K, Dong S, Lonial S, Wang X, Chen GZ, Xie J, Gu T-l, Polakiewicz RD, Roesel JL, Boggon TJ, Khuri FR, Gilliland DG, Cantley LC, Kaufman J, Chen J (2009) Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal 2:ra73CrossRefGoogle Scholar
  18. Horak CE, Lee JH, Marshall JC, Shreeve SM, Steeg PS (2008) The role of metastasis suppressor genes in metastatic dormancy. APMIS 116:586. Scholar
  19. Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134:703. Scholar
  20. Hsu CC, Tseng LM, Lee HC (2016) Role of mitochondrial dysfunction in cancer progression. Exp Biol Med 241:1281–1295. Scholar
  21. Jiang B (2017) Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment. Genes Dis 4:25–27. Scholar
  22. Kato Y, Maeda T, Suzuki A (2018) Cancer metabolism : new insights into classic characteristics. Jpn Dent Sci Rev 54:8–21. Scholar
  23. Kim J-W, Dang CV (2005) Multifaceted roles of glycolytic enzymes. Trends Biochem Sci 30:142–150. Scholar
  24. Kim J-w, Dang CV (2006) Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res 66:8927–8931. Scholar
  25. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185. Scholar
  26. Kondoh H (2012) Glycolytic enzymes can modulate cellular life span. Cancer Res 65:177–186Google Scholar
  27. Legg PD, Chaplin JF, Williamson RE (2010) Genetic diversity in burley and flue-cured Tobacco1. Crop Sci 17:943. Scholar
  28. Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O’Donnell KA, Kim J-w, Yustein JT, Lee LA, Dang CV (2005) Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25:6225–6234. Scholar
  29. Liberti MV, Locasale JW (2016) The Warburg effect : how does it benefit cancer cells ? Trends Biochem Sci 41:211–218. Scholar
  30. Liu W, Beck BH, Vaidya KS, Nash KT, Feeley KP, Ballinger SW, Pounds KM, Denning WL, Diers AR, Landar A, Dhar A, Iwakuma T, Welch DR (2014) Metastasis suppressor KISS1Seemsto reverse the Warburg effect by enhancing mitochondrial biogenesis. Cancer Res 74:954. Scholar
  31. Lu H, Forbes RA, Verma A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277:23111–23115. Scholar
  32. Manley SJ, Liu W, Welch DR (2017) The KISS1 metastasis suppressor appears to reverse the Warburg effect by shifting from glycolysis to mitochondrial beta-oxidation. J Mol Med 95:951. Scholar
  33. Mathupala SP, Ko YH, Pedersen PL (2009) Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg effect” and a pivotal target for effective therapy. Semin Cancer Biol 19:17–24. Scholar
  34. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) P53 regulates mitochondrial respiration. Science 312:1650–1653. Scholar
  35. Miles KA, Williams RE (2008) Warburg revisited : imaging tumour blood flow and. Metabolism 8:81–86. Scholar
  36. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197. Scholar
  37. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2009) The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8:3984–4001. Scholar
  38. Plas DR, Thompson CB (2005) Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24:7435–7442. Scholar
  39. Potter M, Newport E, Morten KJ (2016) The Warburg effect: 80 years on. Biochem Soc Trans 44:1499–1505. Scholar
  40. Samudio I, Fiegl M, Andreeff M (2009) Mitochondrial uncoupling and the Warburg effect: molecular basis for the reprogramming of cancer cell metabolism. Cancer Res 69:2163–2166. Scholar
  41. Sawayama H, Ishimoto T, Sugihara H, Miyanari N, Miyamoto Y, Baba Y, Yoshida N, Baba H (2014) Clinical impact of the Warburg effect in gastrointestinal cancer (Review). Int J Oncol 45:1345–1354. Scholar
  42. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732. Scholar
  43. Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20:51–56. Scholar
  44. Shan M, Dai D, Vudem A, Varner JD, Stroock AD (2018) Multi-scale computational study of the Warburg effect, reverse Warburg effect and glutamine addiction in solid tumors. PLoS Comput Biol 14:1–30. Scholar
  45. Shanmugam M, McBrayer SK, Rosen ST (2009) Targeting the Warburg effect in hematological malignancies: from PET to therapy. Curr Opin Oncol 21:531–536. Scholar
  46. Siddiqui FA, Prakasam G, Chattopadhyay S, Rehman AU, Padder RA, Ansari MA, Irshad R, Mangalhara K, Bamezai RNK, Husain M, Ali SM, Iqbal MA (2018) Curcumin decreases Warburg effect in cancer cells by down-regulating pyruvate kinase M2 via mTOR-HIF1$α$ inhibition. Sci Rep 8:2–10. Scholar
  47. Tran Q, Lee H, Park J, Kim S-h, Park J (2016) Targeting cancer metabolism – revisiting the Warburg effects. Toxicol Res 32:177–193. Scholar
  48. Vander Heiden MG (2012) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029. Scholar
  49. Vazquez A, Liu J, Zhou Y, Oltvai ZN (2010) Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited. BMC Syst Biol 4:58CrossRefGoogle Scholar
  50. Vyas S, Zaganjor E, Haigis MC (2016) Mitochondria and cancer. Cell 166:555–566. Scholar
  51. Wang L, Wang J, Xiong H, Wu F, Lan T, Zhang Y, Guo X, Wang H, Saleem M, Jiang C, Lu J, Deng Y (2016) Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer. EBioMedicine 7:50–61. Scholar
  52. Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8(6):519–530Google Scholar
  53. Wilde L, Roche M, Domingo-Vidal M, Tanson K, Philp N, Curry J, Martinez-Outschoorn U (2017) Metabolic coupling and the reverse Warburg effect in cancer: implications for novel biomarker and anticancer agent development. Semin Oncol 44:198–203. Scholar
  54. Wu WKK, Coffelt SB, Cho CH, Wang XJ, Lee CW, Chan FKL, Yu J, Sung JJY (2012) The autophagic paradox in cancer therapy. Oncogene 31:939–953. Scholar
  55. Wu C-A, Chao Y, Shiah S-G, Lin W-W (2013) Nutrient deprivation induces the Warburg effect through ROS/AMPK-dependent activation of pyruvate dehydrogenase kinase. Biochim Biophys Acta 1833:1147–1156. Scholar
  56. Yang W, Lu Z (2013) Nuclear PKM2 regulates the Warburg effect. Cell Cycle 12:3154–3158. Scholar
  57. Yoshida GJ (2015) Metabolic reprogramming: the emerging concept and associated therapeutic strategies. J Exp Clin Cancer Res 34:1–10. Scholar
  58. Yu L, Chen X, Sun X, Wang L, Chen S (2017) The glycolytic switch in tumors: how many players are involved? J Cancer 8:3430–3440. Scholar
  59. Zawacka-Pankau J, Grinkevich VV, Hünten S, Nikulenkov F, Gluch A, Li H, Enge M, Kel A, Selivanova G (2011) Inhibition of glycolytic enzymes mediated by pharmacologically activated p53. J Biol Chem 286:41600–41615. Scholar
  60. Zhang C, Liu J, Liang Y, Wu R, Zhao Y, Hong X, Lin M, Yu H, Liu L, Levine AJ, Hu W, Feng Z (2013) Tumour-associated mutant p53 drives the Warburg effect. Nat Commun 4:2935. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Samyukta Narayanan
    • 1
  • Anirudh Santhoshkumar
    • 1
  • Srijit Ray
    • 1
  • Sitaram Harihar
    • 1
  1. 1.Department of Genetic Engineering, School of BioengineeringSRM Institute of Science and TechnologyKattankulathurIndia

Personalised recommendations