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Otto Warburg's contributions to current concepts of cancer metabolism

An Erratum to this article was published on 14 July 2011

This article has been updated

Key Points

  • Otto Warburg was a pioneering biochemistry researcher who made substantial contributions to our early understanding of cancer metabolism. Warburg was awarded the Nobel Prize in Physiology or Medicine in 1931 for his discovery of cytochrome c oxidase, not for his work on cancer and the formulation of the Warburg hypothesis.

  • The Warburg effect is the reverse of the Pasteur effect (the inhibition of fermentation by O2) exhibited by cancer cells; alteration of the Pasteur effect in cancer is linked to prolyl hydroxylases and hypoxia-inducible factor (HIF).

  • Tumour suppressors and oncogenes converge on HIF to reverse the Pasteur effect and thereby induce the Warburg effect.

  • Cancer cells carry out aerobic glycolysis and respiration concurrently.

  • Tumour suppressors and oncogenes exert direct effects on metabolism: p53 promotes the pentose phosphate pathway and oxidative phosphorylation; MYC induces glycolysis and glutamine metabolism.

  • Mutations in metabolic enzymes, specifically isocitrate dehydrogenase 1 (IDH1) and IDH2 and other citric acid cycle enzymes, are causally linked to familial and spontaneous cancers.

Abstract

Otto Warburg pioneered quantitative investigations of cancer cell metabolism, as well as photosynthesis and respiration. Warburg and co-workers showed in the 1920s that, under aerobic conditions, tumour tissues metabolize approximately tenfold more glucose to lactate in a given time than normal tissues, a phenomenon known as the Warburg effect. However, this increase in aerobic glycolysis in cancer cells is often erroneously thought to occur instead of mitochondrial respiration and has been misinterpreted as evidence for damage to respiration instead of damage to the regulation of glycolysis. In fact, many cancers exhibit the Warburg effect while retaining mitochondrial respiration. We re-examine Warburg's observations in relation to the current concepts of cancer metabolism as being intimately linked to alterations of mitochondrial DNA, oncogenes and tumour suppressors, and thus readily exploitable for cancer therapy.

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Figure 1: Otto Warburg.
Figure 2: Grant proposal.
Figure 3: The reaction vessel for tissue slices developed by Otto Warburg and representative data.
Figure 4: The regulation of metabolism in cancer.
Figure 5: The effects on glucose and glutamine metabolism.

Change history

  • 14 July 2011

    The acknowledgement for the source of Figure 1 on page 327 of this article was incorrect and has now been corrected online.

References

  1. Werner, P. Ein Genie irrt seltener. Otto Heinrich Warburg. Ein Lebensbild in Dokumenten (Akademie Verlag, Berlin, 1991).

    Google Scholar 

  2. Warburg, O. Über den Stoffwechsel der Carcinomzelle. Klin. Wochenschr. 4, 534–536 (1925).

    CAS  Article  Google Scholar 

  3. Keilin, D. The History of Cell Respiration and Cytochrome (Cambridge Univ. Press, Cambridge, 1970).

    Google Scholar 

  4. Racker, E. Bioenergetics and the problem of tumor growth. Am. Sci. 60, 56–63 (1972). In this paper, Racker coins the term “the Warburg effect” in describing his own hypothesis on the origins of tumour growth.

    CAS  PubMed  Google Scholar 

  5. Turner, J. S. & Brittain, E. G. Oxygen as a factor in photosynthesis. Biol. Rev. 37, 130–170 (1962).

    CAS  PubMed  Article  Google Scholar 

  6. Pedersen, P. L. The cancer cell's “power plants” as promising therapeutic targets: an overview. J. Bioenerg. Biomembr. 39, 1–12 (2007).

    CAS  PubMed  Article  Google Scholar 

  7. Warburg, O. On respiratory impairment in cancer cells. Science 124, 269–270 (1956).

    CAS  PubMed  Article  Google Scholar 

  8. Krebs, H. Otto Heinrich Warburg. 1883–1970. Biogr. Mems Fell. R. Soc. 18, 628–699 (1972). An excellent English-language biography of Otto Warburg.

    Article  Google Scholar 

  9. Krebs, H. Otto Warburg, Zellphysiologe, Biochemiker, Mediziner (Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1979).

    Google Scholar 

  10. Werner, P. Otto Warburg. Von der Zellphysiologie zur Krebsforschung (Verlag Neues Leben, Berlin, 1988).

    Google Scholar 

  11. Höxtermann, E. & Sucker, U. Otto Warburg (BSB B. G. Teubner Verlagsgesellschaft, Leipzig, 1989).

    Book  Google Scholar 

  12. Koepcke, C. Lotte Warburg (Iudicium, München, 2000).

    Google Scholar 

  13. Einstein, A. Emil Warburg als Forscher. Naturwiss. 10, 823–826 (1922).

    CAS  Article  Google Scholar 

  14. Warburg, O. Versuche an überlebendem Carcinom-Gewebe (Methoden). Biochem. Zeitschr. 142, 317–333 (1923).

    CAS  Google Scholar 

  15. Warburg, O. Über den Stoffwechsel der Tumoren. Arbeiten aus dem Kaiser Wilhelm-Institut für Biologie - Berlin-Dahlem (Julius Springer, Berlin, 1926).

    Google Scholar 

  16. Sri Kantha, S. The question of nepotism in the award of Nobel prizes: a critique of the view of Hans Krebs. Med. Hypotheses 34, 28–32 (1991).

    CAS  PubMed  Article  Google Scholar 

  17. Warburg, O. Notizen zur Entwickelungsphysiologie des Seeigeleies. Arch. f. d. ges. Physiol. 160, 324–332 (1915).

    CAS  Article  Google Scholar 

  18. Warburg, O. Verbesserte Methode zur Messung der Atmung und Glykolyse. Biochem. Zeitschr. 152, 51–63 (1924).

    CAS  Google Scholar 

  19. Minami, S. Versuche an überlebendem Carcinomgewebe. Biochem. Zeitschr. 142, 334–350 (1923).

    CAS  Google Scholar 

  20. Warburg, O., Posener, K. & Negelein, E. Über den Stoffwechsel der Carcinomzelle. Biochem. Zeitschr. 152, 309–344 (1924). In this landmark paper, Warburg and co-workers reported quantitative descriptions of respiration and lactic acid production measured by manometry in a variety of normal, embryonic and cancerous tissues.

    CAS  Google Scholar 

  21. Freyer, J. P., Tustanoff, E., Franko, A. J. & Sutherland, R. M. In situ oxygen consumption rates in V-79 multicellular spheroids during growth. J. Cell. Physiol. 118, 53–61 (1984).

    CAS  PubMed  Article  Google Scholar 

  22. Braun, R. D. & Beatty, A. L. Modeling of oxygen transport across tumor multicellular layers. Microvasc. Res. 73, 113–123 (2007).

    CAS  PubMed  Article  Google Scholar 

  23. Warburg, O. & Hiepler, E. Versuche mit Ascites-Tumorzellen. Z. Naturforsch. 7b, 193–194 (1952).

    CAS  Google Scholar 

  24. Chance, B. & Castor, L. N. Some patterns of the respiratory pigments of ascites tumors in mice. Science 116, 200–202 (1952).

    CAS  PubMed  Article  Google Scholar 

  25. Chance, B. & Hess, B. Spectroscopic evidence of metabolic control. Science 129, 700–708 (1959).

    CAS  PubMed  Article  Google Scholar 

  26. Weinhouse, S. On respiratory impairment in cancer cells. Science 124, 267–269 (1956).

    CAS  PubMed  Article  Google Scholar 

  27. Burk, D. & Schade, A. L. On respiratory impairment in cancer cells. Science 124, 270–272 (1956).

    CAS  PubMed  Article  Google Scholar 

  28. Cori, C. F. & Cori, G. T. The carbohydrate metabolism of tumors. I. The free sugar, lactic acid, and glycogen content of malignant tumors. J. Biol. Chem. 64, 11–22 (1925).

    CAS  Article  Google Scholar 

  29. Warburg, O., Wind, F. & Negelein, E. Über den Stoffwechsel der Tumoren in Körper. Klinische Wochenschrift 5, 829–832 (1926).

    CAS  Article  Google Scholar 

  30. Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927). Reference 29 is an important work in which the consumption of glucose and production of lactic acid in tumours transplanted in rats were measured directly and compared with the corresponding metabolism by normal tissues. Reference 30 is an English translation of reference 29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Cori, C. F. & Cori, G. T. The carbohydrate metabolism of tumors. II. Changes in the sugar, lactic acid, and co-combining power of blood passing through a tumor. J. Biol. Chem. 65, 397–405 (1925).

    CAS  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Warburg, O. Über den heutigen Stand des Carcinomproblems. Naturwiss. 15, 1–4 (1927).

    CAS  Article  Google Scholar 

  34. Crabtree, H. G. Observations on the carbohydrate metabolism of tumors. Biochem. J. 23, 536–545 (1929).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Warburg, O. in New Methods of Cell Physiology Applied to Cancer, Photosynthesis, and Mechanism of X-Ray Action. Developed 1945–1961 (ed. Warburg, O.) 631–632 (Interscience Publishers, New York, 1962). This book contains reprints of Warburg's work on both cancer cell metabolism and photosynthesis published from 1945–1961. Most contributions are in German, but some are in English, including a three-part forum “On respiratory impairment in cancer cells” that appeared in Science in 1956. In the penultimate chapter of the book, Warburg revises his classification of cancer cells as cells in which respiration is insufficient rather than impaired.

  36. Koppenol, W. H. & Bounds, P. L. The Warburg effect and metabolic efficiency: re-crunching the numbers. Science [online], (2009).

  37. Elstrom, R. L. et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 64, 3892–3899 (2004).

    CAS  Article  PubMed  Google Scholar 

  38. Varmus, H., Pao, W., Politi, K., Podsypanina, K. & Du, Y. C. Oncogenes come of age. Cold Spring Harb. Symp. Quant. Biol. 70, 1–9 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Land, H., Parada, L. F. & Weinberg, R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304, 596–602 (1983).

    CAS  PubMed  Article  Google Scholar 

  40. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008). This seminal paper reports frequent mutations in IDH1 and IDH2 in human brain cancer.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  42. Nachmansohn, D. German-Jewish Pioneers in Science, 1900–1933 (Springer, New York, 1979).

    Book  Google Scholar 

  43. Hao, H. X. et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325, 1139–1142 (2009).

    CAS  Article  PubMed  Google Scholar 

  44. King, A., Selak, M. A. & Gottlieb, E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25, 4675–4682 (2006).

    CAS  Article  PubMed  Google Scholar 

  45. Seagroves, T. N. et al. Transcription factor HIF-1 is a necessary mediator of the Pasteur effect in mammalian cells. Mol. Cell. Biol. 21, 3436–3444 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).

    CAS  PubMed  Article  Google Scholar 

  47. Firth, J. D., Ebert, B. L., Pugh, C. W. & Ratcliffe, P. J. Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3′ enhancer. Proc. Natl Acad. Sci. USA 91, 6496–6500 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. Semenza, G. L., Roth, P. H., Fang, H.-M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994).

    CAS  PubMed  Article  Google Scholar 

  49. Reitman, Z. J. & Yan, H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J. Natl Cancer Inst. 102, 932–941 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Zhao, S. et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324, 261–265 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). This paper reports the neomorphic activity of mutant IDH1, which produces 2-hydroxyglutarate from oxoglutarate.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. He, Y. et al. Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 464, 610–614 (2010). This paper reports the comprehensive analysis of mtDNA mutations occurring in normal and tumour cells, illustrating the natural occurrence of mtDNA mutations during embryogenesis.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Petros, J. A. et al. mtDNA mutations increase tumorigenicity in prostate cancer. Proc. Natl Acad. Sci. USA 102, 719–724 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. Zhou, S. et al. Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck. Proc. Natl Acad. Sci. USA 104, 7540–7545 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. Park, J. S. et al. A heteroplasmic, not homoplasmic, mitochondrial DNA mutation promotes tumorigenesis via alteration in reactive oxygen species generation and apoptosis. Hum. Mol. Genet. 18, 1578–1589 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Ishikawa, K. et al. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320, 661–664 (2008).

    CAS  PubMed  Article  Google Scholar 

  60. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg Effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Hsu, P. P. & Sabatini, D. M. Cancer cell metabolism: Warburg and beyond. Cell 134, 703–707 (2008).

    CAS  PubMed  Article  Google Scholar 

  62. Semenza, G. L. HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20, 51–56 (2010). This paper provides a comprehensive review of HIF1 as a critical node in reprogramming cancer metabolism.

    CAS  PubMed  Article  Google Scholar 

  63. Deberardinis, R. J., Sayed, N., Ditsworth, D. & Thompson, C. B. Brick by brick: metabolism and tumor cell growth. Curr. Opin. Genet. Dev. 18, 54–61 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Levine, A. J. & Puzio-Kuter, A. M. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330, 1340–1344 (2010).

    CAS  PubMed  Article  Google Scholar 

  65. Cooper, J. A., Esch, F. S., Taylor, S. S. & Hunter, T. Phosphorylation sites in enolase and lactate dehydrogenase utilized by tyrosine protein kinases in vivo and in vitro. J. Biol. Chem. 259, 7835–7841 (1984).

    CAS  PubMed  Article  Google Scholar 

  66. Flier, J. S., Mueckler, M. M., Usher, P. & Lodish, H. F. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 235, 1492–1495 (1987).

    CAS  Article  PubMed  Google Scholar 

  67. Gleadle, J. M. & Ratcliffe, P. J. Induction of hypoxia-inducible factor-1, erythropoietin, vascular endothelial growth factor, and glucose transporter-1 by hypoxia: evidence against a regulatory role for Src kinase. Blood 89, 503–509 (1997).

    CAS  Article  PubMed  Google Scholar 

  68. Jiang, B.-H., Agani, F., Passaniti, A. & Semenza, G. L. 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, 5328–5335 (1997).

    CAS  PubMed  Google Scholar 

  69. Osthus, R. C. et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J. Biol. Chem. 275, 21797–21800 (2000).

    CAS  Article  PubMed  Google Scholar 

  70. Ahuja, P. et al. Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice. J. Clin. Invest. 120, 1494–1505 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Shim, H. et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl Acad. Sci. USA 94, 6658–6663 (1997). This paper reports the first direct link between the oncogene MYC and the regulation of energy metabolism.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

    CAS  PubMed  Article  Google Scholar 

  73. Mazurek, S., Boschek, C. B., Hugo, F. & Eigenbrodt, E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin. Cancer Biol. 15, 300–308 (2005).

    CAS  Article  PubMed  Google Scholar 

  74. David, C. J., Chen, M., Assanah, M., Canoll, P. & Manley, J. L. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463, 364–368 (2010). References 72–74 document the role of PKM2, an alternatively spliced form of PK, in cancer metabolism.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Robey, R. B. & Hay, N. Is Akt the “Warburg kinase”? — Akt: energy metabolism interactions and oncogenesis. Semin. Cancer Biol. 19, 25–31 (2009).

    CAS  Article  PubMed  Google Scholar 

  77. Deprez, J., Vertommen, D., Alessi, D. R., Hue, L. & Rider, M. H. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J. Biol. Chem. 272, 17269–17275 (1997).

    CAS  PubMed  Article  Google Scholar 

  78. Arsham, A. M., Plas, D. R., Thompson, C. B. & Simon, M. C. Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1a nor sufficient for HIF-1-dependent target gene transcription. J. Biol. Chem. 277, 15162–15170 (2002).

    CAS  PubMed  Article  Google Scholar 

  79. Arsham, A. M., Plas, D. R., Thompson, C. B. & Simon, M. C. Akt and hypoxia-inducible factor-1 independently enhance tumor growth and angiogenesis. Cancer Res. 64, 3500–3507 (2004).

    CAS  PubMed  Article  Google Scholar 

  80. Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C. & Semenza, G. L. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol. Cell. Biol. 21, 3995–4004 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Fan, Y., Dickman, K. G. & Zong, W. X. Akt and c-Myc differentially activate cellular metabolic programs and prime cells to bioenergetic inhibition. J. Biol. Chem. 285, 7324–7333 (2010).

    CAS  Article  PubMed  Google Scholar 

  82. Robey, I. F. et al. Regulation of the Warburg effect in early-passage breast cancer cells. Neoplasia 10, 745–756 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555–1559 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Ramanathan, A., Wang, C. & Schreiber, S. L. Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc. Natl Acad. Sci. USA 102, 5992–5997 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Kikuchi, H., Pino, M. S., Zeng, M., Shirasawa, S. & Chung, D. C. Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1α and -2α in colon cancer. Cancer Res. 69, 8499–8506 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Sears, R., Leone, G., DeGregori, J. & Nevins, J. R. Ras enhances Myc protein stability. Mol. Cell 3, 169–179 (1999).

    CAS  PubMed  Article  Google Scholar 

  87. Gordan, J. D. et al. HIF-α effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14, 435–446 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Zundel, W. et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391–396 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Blagosklonny, M. V. et al. p53 Inhibits hypoxia-inducible factor-stimulated transcription. J. Biol. Chem. 273, 11995–11998 (1998).

    CAS  PubMed  Article  Google Scholar 

  90. Agani, F., Kirsch, D. G., Friedman, S. L., Kastan, M. B. & Semenza, G. L. p53 does not repress hypoxia-induced transcription of the vascular endothelial growth factor gene. Cancer Res. 57, 4474–4477 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  92. Vousden, K. H. & Ryan, K. M. p53 and metabolism. Nature Rev. Cancer 9, 691–700 (2009).

    CAS  Article  Google Scholar 

  93. Cheung, E. C. & Vousden, K. H. The role of p53 in glucose metabolism. Curr. Opin. Cell Biol. 22, 186–191 (2010).

    CAS  PubMed  Article  Google Scholar 

  94. Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006).

    CAS  Article  PubMed  Google Scholar 

  95. Ruiz-Lozano, P. et al. p53 is a transcriptional activator of the muscle-specific phosphoglycerate mutase gene and contributes in vivo to the control of its cardiac expression. Cell Growth Differ. 10, 295–306 (1999). This paper, reference 92 and reference 94 link p53 to glucose metabolism and mitochondrial function.

    CAS  PubMed  Google Scholar 

  96. Brand, K. Glutamine and glucose metabolism during thymocyte proliferation. Pathways of glutamine and glutamate metabolism. Biochem. J. 228, 353–361 (1985).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Newsholme, E. A., Crabtree, B. & Ardawi, M. S. M. Glutamine metabolism in lymphocytes: its biochemical, physiological and clinical importance. Q. J. Exp. Physiol. 70, 473–489 (1985).

    CAS  PubMed  Article  Google Scholar 

  98. Moreadith, R. W. & Lehninger, A. L. The pathway of glutamate and glutamine oxidation by tumor cell mitochondria. Role of mitochondrial NAD(P)+-dependent malic enzyme. J. Biol. Chem. 259, 6215–6221 (1984).

    CAS  PubMed  Article  Google Scholar 

  99. Deberardinis, R. J. & Cheng, T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313–324 (2010).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Wise, D. R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA 105, 18782–18787 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. Yuneva, M., Zamboni, N., Oefner, P., Sachidanandam, R. & Lazebnik, Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J. Cell. Biol. 178, 93–105 (2007). References 100–102 link MYC to the regulation of glutamine metabolism and glutamine dependency.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Wang, J. B. et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 207–219 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788–8793 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Cadoret, A. et al. New targets of β-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene 21, 8293–8301 (2002).

    CAS  PubMed  Article  Google Scholar 

  106. Matsuno, T. & Goto, I. Glutaminase and glutamine synthetase activities in human cirrhotic liver and hepatocellular carcinoma. Cancer Res. 52, 1192–1194 (1992).

    CAS  PubMed  Google Scholar 

  107. Linder-Horowitz, M., Knox, W. E. & Morris, H. P. Glutaminase activities and growth rates of rat hepatomas. Cancer Res. 29, 1195–1199 (1969).

    CAS  PubMed  Google Scholar 

  108. Dal Bello, B. et al. Glutamine synthetase immunostaining correlates with pathologic features of hepatocellular carcinoma and better survival after radiofrequency thermal ablation. Clin. Cancer Res. 16, 2157–2166 (2010).

    CAS  PubMed  Article  Google Scholar 

  109. Burke, Z. D. et al. Liver zonation occurs through a β-catenin-dependent, c-Myc-independent mechanism. Gastroenterology 136, 2316–2324 (2009).

    CAS  PubMed  Article  Google Scholar 

  110. Vousden, K. H. Alternative fuel — another role for p53 in the regulation of metabolism. Proc. Natl Acad. Sci. USA 107, 7117–7118 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Suzuki, S. et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc. Natl Acad. Sci. USA 107, 7461–7466 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Greiner, E. F., Guppy, M. & Brand, K. Glucose is essential for proliferation and the glycolytic enzyme induction that provokes a transition to glycolytic energy production. J. Biol. Chem. 269, 31484–31490 (1994).

    CAS  PubMed  Article  Google Scholar 

  115. Lemons, J. M. et al. Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol. 8, e1000514 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  116. Shim, H., Chun, Y. S., Lewis, B. C. & Dang, C. V. A unique glucose-dependent apoptotic pathway induced by c-Myc. Proc. Natl Acad. Sci. USA 95, 1511–1516 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. Lippman, S. I. & Broach, J. R. Protein kinase A and TORC1 activate genes for ribosomal biogenesis by inactivating repressors encoded by Dot6 and its homolog Tod6. Proc. Natl Acad. Sci. USA 106, 19928–19933 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. Rabinowitz, J. D. & White, E. Auophagy and metabolism. Science 330, 1344–1348 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Le, A. et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA 107, 2037–2042 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. Michelakis, E. D. et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2, 31ra34 (2010).

    CAS  PubMed  Article  Google Scholar 

  121. Dang, C. V. Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res. 70, 859–862 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. Kim, J. W., Gao, P., Liu, Y. C., Semenza, G. L. & Dang, C. V. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol. Cell. Biol. 27, 7381–7393 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. Funes, J. M. et al. Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production. Proc. Natl Acad. Sci. USA 104, 6223–6228 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. Fogal, V. et al. Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol. Cell. Biol. 30, 1303–1318 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Kroemer, G. & Pouyssegur, J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 13, 472–482 (2008).

    CAS  PubMed  Article  Google Scholar 

  126. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nature Rev. Cancer 11, 85–95 (2011).

    CAS  Article  Google Scholar 

  127. Tennant, D. A., Durán, R. V. & Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nature Rev. Cancer 10, 267–277 (2010). This is a comprehensive critical Review of the emerging area of therapeutic targeting of cancer metabolism.

    CAS  Article  Google Scholar 

  128. Thornburg, J. M. et al. Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res. 10, R84 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. Krogh, A. The rate of diffusion of gases through animal tissues, with some remarks on the coefficient of invasion. J. Physiol. 52, 391–408 (1919).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Warburg, O. Über Milchsäurebildung beim Wachstum. Biochem. Zeitschr. 160, 307–311 (1925).

    CAS  Google Scholar 

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Acknowledgements

We thank John Eaton for instigating this collaborative Review. The authors' work is partially funded by US National Cancer Institute grants (C.V.D.), the Leukemia Lyphoma Society (C.V.D.) and an American Association for Cancer Research 'Stand Up To Cancer' translational grant (C.V.D.). We also acknowledge support by the Swiss Federal Institute of Technology Zurich (P.L.B. and W.H.K.).

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Correspondence to Willem H. Koppenol or Chi V. Dang.

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C.V.D. is a consultant for Agios Pharmaceuticals, Inc. W.H.K. and P.L.B. declare no competing financial interests.

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Glossary

Respiration

The metabolic process by which energy is produced in the presence of O2 through the oxidation of organic compounds (typically sugars) to CO2 and H2O by glycolysis, the citric acid cycle and oxidative phosphorylation.

Glycolysis

A metabolic pathway that occurs in the cell cytoplasm and involves a sequence of ten enzymatic reactions. These reactions convert glucose to pyruvate and produce the high-energy compounds ATP and NADH.

Pasteur effect

Pasteur's observation that yeast cells consume less sugar when grown in the presence of O2 than when grown in the absence of it.

Fermentation

The metabolic process by which energy is produced in the absence of O2 through the oxidation of organic compounds, typically sugars, to simpler organic compounds, such as pyruvate. Pyruvate is further processed to ethanol by alcoholic fermentation or lactic acid by lactate fermentation; see 'glycolysis'.

Warburg effect

A term used to describe two unrelated observations in plant physiology and oncology, both from the work of Otto Warburg. In oncology, the Warburg effect refers to the high rate of glycolysis and lactate fermentation in the cytosol exhibited by most cancer cells, relative to the comparatively low rate of glycolysis and oxidation of pyruvate in mitochondria exhibited by most normal cells. In plant physiology, the Warburg effect is the inhibition of photosynthetic CO2 fixation by high concentrations of O2.

Habilitation

A quasi-independent postdoctoral appointment that is required for further academic advancement in German-speaking countries.

Citric acid cycle

A cyclic series of eight enzymatic reactions that occur in the mitochondrial matrix and that convert acetyl CoA derived from carbohydrates, fatty acids and amino acids to CO2 and H2O; also known as the tricarboxylic acid (TCA) cycle or Krebs cycle.

Aerobic glycolysis

The enzymatic transformation of glucose to pyruvate in the presence of O2; see 'glycolysis'.

Oxidative phosphorylation

(OXPHOS). A metabolic process that occurs in mitochondria. It produces energy in the form of ATP from ADP and inorganic phosphate, and is driven by a proton gradient generated by the reactions of the citric acid cycle.

Heteroplasmy

The situation in which the many hundreds of mitochondria within a single eukaryotic cell are a mixture of those that contain mutant mitochondrial DNA (mtDNA) and normal mtDNA. Heteroplasmy has a role in the severity of mitochondrial diseases.

Homoplasmy

The situation in which a mutation in mitochondrial DNA is present in all of the mitochondria within a single eukaryotic cell.

Anaerobic glycolysis

The enzymatic transformation of glucose to pyruvate in the absence of O2; see 'glycolysis'.

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Koppenol, W., Bounds, P. & Dang, C. Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 11, 325–337 (2011). https://doi.org/10.1038/nrc3038

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