Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?

Key Points

  • Cancer cells display high aerobic glycolysis despite oxidative phosphorylation.

  • High aerobic glycolysis distinguishes cancer cells from normal cells, and is exploited to detect tumours in vivo.

  • Cancer cells increase glucose flux to meet anabolic demands and to maintain the redox state.

  • Cancer cells preferentially express transporters and enzyme isoforms that drive glucose flux forwards.

  • Selective targeting of glucose metabolism for cancer therapy is challenging, but possible.

  • As a proof of concept, hexokinase 2 (HK2), which is preferentially expressed by cancer cells, can be systemically deleted in mice for cancer therapy and without adverse consequences.

  • It is possible that in the future, targeting glucose metabolism will be used as adjuvant therapy together with existing cancer therapeutic approaches.

Abstract

In recent years there has been a growing interest among cancer biologists in cancer metabolism. This Review summarizes past and recent advances in our understanding of the reprogramming of glucose metabolism in cancer cells, which is mediated by oncogenic drivers and by the undifferentiated character of cancer cells. The reprogrammed glucose metabolism in cancer cells is required to fulfil anabolic demands. This Review discusses the possibility of exploiting the reprogrammed glucose metabolism for therapeutic approaches that selectively target cancer cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Changes that occur in glucose metabolism of cancer cells.
Figure 2: Branching pathways from glucose-6-phosphate.
Figure 3: The serine biosynthesis pathway and extensions to the one-carbon metabolism, the methionine cycle, the purine biosynthesis pathway and the generation of glutathione.
Figure 4: Positive and negative regulation of enzymes in glucose metabolism.
Figure 5: Regulation of glucose metabolism by oncoproteins and tumour suppressors.
Figure 6: Reprogramming of glucose metabolism in hepatocellular carcinoma.
Figure 7: Energetic and oxidative stress during solid tumour formation.

Similar content being viewed by others

References

  1. Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Warburg, O. The Metabolism of Tumours: Investigations from the Kaiser Wilhelm Institute for Biology, Berlin-Dahlen (Constable, 1930).

    Google Scholar 

  3. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Weinhouse, S. Studies on the fate of isotopically labeled metabolites in the oxidative metabolism of tumors. Cancer Res. 11, 585–591 (1951). References 3–6 include the original Warburg theory that respiration is impaired in cancer cells followed by the debate between Warburg and Weinhouse on whether respiration is impaired in cancer cells, and a paper by Weinhouse describing the use of isotope tracing to determine oxidative metabolism in tumours.

    CAS  PubMed  Google Scholar 

  7. Weinhouse, S. Oxidative metabolism of neoplastic tissues. Adv. Cancer Res. 3, 269–325 (1955).

    Article  CAS  PubMed  Google Scholar 

  8. Weinhouse, S. Glycolysis, respiration, and anomalous gene expression in experimental hepatomas: G. H. A. Clowes memorial lecture. Cancer Res. 32, 2007–2016 (1972).

    CAS  PubMed  Google Scholar 

  9. Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg's contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 11, 325–337 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Crabtree, H. G. The carbohydrate metabolism of certain pathological overgrowths. Biochem. J. 22, 1289–1298 (1928).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Patra, K. C. & Hay, N. The pentose phosphate pathway and cancer. Trends Biochem. Sci. 39, 347–354 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Timm, K. N. et al. Hyperpolarized [U-2H, U-13C]Glucose reports on glycolytic and pentose phosphate pathway activity in EL4 tumors and glycolytic activity in yeast cells. Magn. Reson. Med. 74, 1543–1547 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Love, D. C. & Hanover, J. A. The hexosamine signaling pathway: deciphering the “O-GlcNAc code”. Sci. STKE 312, re13 (2005).

    Google Scholar 

  14. Hanover, J. A., Krause, M. W. & Love, D. C. The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine. Biochim. Biophys. Acta 1800, 80–95 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Jozwiak, P., Forma, E., Brys, M. & Krzeslak, A. O-GlcNAcylation and metabolic reprogramming in cancer. Front. Endocrinol. (Lausanne) 5, 145 (2014).

    Google Scholar 

  16. Zois, C. E., Favaro, E. & Harris, A. L. Glycogen metabolism in cancer. Biochem. Pharmacol. 92, 3–11 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Patra, K. C. & Hay, N. Hexokinase 2 as oncotarget. Oncotarget 4, 1862–1863 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Patra, K. C. et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24, 213–228 (2013). A demonstration that it is feasible to systemically delete a major glycolytic enzyme for cancer therapy in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Robey, R. B. & Hay, N. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 25, 4683–4696 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Sui, D. & Wilson, J. E. Structural determinants for the intracellular localization of the isozymes of mammalian hexokinase: intracellular localization of fusion constructs incorporating structural elements from the hexokinase isozymes and the green fluorescent protein. Arch. Biochem. Biophys. 345, 111–125 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Wilson, J. E. Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J. Exp. Biol. 206, 2049–2057 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Irwin, D. M. & Tan, H. Molecular evolution of the vertebrate hexokinase gene family: identification of a conserved fifth vertebrate hexokinase gene. Comp. Biochem. Physiol. Part D Genom. Proteom. 3, 96–107 (2008).

    Google Scholar 

  23. Guo, C. et al. Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. Nat. Commun. 6, 6069 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Shinohara, Y., Yamamoto, K., Kogure, K., Ichihara, J. & Terada, H. Steady state transcript levels of the type II hexokinase and type 1 glucose transporter in human tumor cell lines. Cancer Lett. 82, 27–32 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Mathupala, S. P., Rempel, A. & Pedersen, P. L. Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J. Biol. Chem. 276, 43407–43412 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Tsai, H. J. & Wilson, J. E. Functional organization of mammalian hexokinases: both N- and C-terminal halves of the rat type II isozyme possess catalytic sites. Arch. Biochem. Biophys. 329, 17–23 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Israelsen, W. J. & Vander Heiden, M. G. Pyruvate kinase: function, regulation and role in cancer. Semin. Cell Dev. Biol. 43, 43–51 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yamada, K. & Noguchi, T. Nutrient and hormonal regulation of pyruvate kinase gene expression. Biochem. J. 337, 1–11 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Israelsen, W. J. et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155, 397–409 (2013). This paper showed that PKM2 deficiency accelerates mammary tumour formation in a mouse model of breast cancer.

    Article  CAS  PubMed  Google Scholar 

  30. Cortes-Cros, M. et al. M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth. Proc. Natl Acad. Sci. USA 110, 489–494 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, Y. H. et al. Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell 158, 1309–1323 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vander Heiden, M. G. et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329, 1492–1499 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Valvona, C. J., Fillmore, H. L., Nunn, P. B. & Pilkington, G. J. The regulation and function of lactate dehydrogenase a: therapeutic potential in brain tumor. Brain Pathol. 26, 3–17 (2016).

    Article  CAS  PubMed  Google Scholar 

  34. Doherty, J. R. & Cleveland, J. L. Targeting lactate metabolism for cancer therapeutics. J. Clin. Invest. 123, 3685–3692 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Costa Leite, T., Da Silva, D., Guimaraes Coelho, R., Zancan, P. & Sola-Penna, M. Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1- kinase tetramers down-regulating the enzyme and muscle glycolysis. Biochem. J. 408, 123–130 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B. & Gillies, R. J. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 66, 5216–5223 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Fukumura, D. et al. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res. 61, 6020–6024 (2001).

    CAS  PubMed  Google Scholar 

  38. Shi, Q. et al. Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene 20, 3751–3756 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Baumann, F. et al. Lactate promotes glioma migration by TGF-β2-dependent regulation of matrix metalloproteinase-2. Neuro Oncol. 11, 368–380 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rozhin, J., Sameni, M., Ziegler, G. & Sloane, B. F. Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res. 54, 6517–6525 (1994).

    CAS  PubMed  Google Scholar 

  41. Feron, O. Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother. Oncol. 92, 329–333 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Hirschhaeuser, F., Sattler, U. G. & Mueller-Klieser, W. Lactate: a metabolic key player in cancer. Cancer Res. 71, 6921–6925 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. Hensley, C. T., Wasti, A. T. & DeBerardinis, R. J. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J. Clin. Invest. 123, 3678–3684 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 43, 869–874 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011). References 45 and 46 showed overexpression of PHGDH in cancer cells, which diverts metabolism into the serine biosynthesis pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gromova, I. et al. High level PHGDH expression in breast is predominantly associated with keratin 5-positive cell lineage independently of malignancy. Mol. Oncol. 9, 1636–1654 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sun, L. et al. cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. Cell Res. 25, 429–444 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen, J. et al. Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth. Oncotarget 4, 2502–2511 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Pacold, M. E. et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat. Chem. Biol. 12, 452–458 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fan, J. et al. Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510, 298–302 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lewis, C. A. et al. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol. Cell 55, 253–263 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hitosugi, T. et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell 22, 585–600 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dunaway, G. A., Kasten, T. P., Sebo, T. & Trapp, R. Analysis of the phosphofructokinase subunits and isoenzymes in human tissues. Biochem. J. 251, 677–683 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ros, S. & Schulze, A. Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism. Cancer Metab. 1, 8 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Chesney, J. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase and tumor cell glycolysis. Curr. Opin. Clin. Nutr. Metab. Care 9, 535–539 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Yi, W. et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337, 975–980 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278–1283 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Seidler, N. W. Basic biology of GAPDH. Adv. Exp. Med. Biol. 985, 1–36 (2013).

    Article  PubMed  Google Scholar 

  61. Semenza, G. L. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Invest. 123, 3664–3671 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen, C., Pore, N., Behrooz, A., Ismail-Beigi, F. & Maity, A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J. Biol. Chem. 276, 9519–9525 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555–1559 (2009). This paper showed that the oncogenic activity of KRAS or BRAF requires GLUT1 and that glucose deprivation can induce oncogenic KRAS or BRAF mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Barthel, A. et al. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J. Biol. Chem. 274, 20281–20286 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Foran, P. G. et al. Protein kinase B stimulates the translocation of GLUT4 but not GLUT1 or transferrin receptors in 3T3-L1 adipocytes by a pathway involving SNAP-23, synaptobrevin-2, and/or cellubrevin. J. Biol. Chem. 274, 28087–28095 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Von der Crone, S. et al. Glucose deprivation induces Akt-dependent synthesis and incorporation of GLUT1, but not of GLUT4, into the plasma membrane of 3T3-L1 adipocytes. Eur. J. Cell Biol. 79, 943–949 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Katabi, M. M., Chan, H. L., Karp, S. E. & Batist, G. Hexokinase type II: a novel tumor-specific promoter for gene-targeted therapy differentially expressed and regulated in human cancer cells. Hum. Gene Ther. 10, 155–164 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Pedersen, P. L., Mathupala, S., Rempel, A., Geschwind, J. F. & Ko, Y. H. Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim. Biophys. Acta 1555, 14–20 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gottlob, K. et al. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 15, 1406–1418 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Miyamoto, S., Murphy, A. N. & Brown, J. H. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ. 15, 521–529 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Minchenko, A. et al. Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose- 2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. J. Biol. Chem. 277, 6183–6187 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Atsumi, T. et al. High expression of inducible 6-phosphofructo-2-kinase/fructose- 2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res. 62, 5881–5887 (2002).

    CAS  PubMed  Google Scholar 

  74. Minchenko, O. H. et al. Overexpression of 6-phosphofructo-2-kinase/fructose- 2,6-bisphosphatase-4 in the human breast and colon malignant tumors. Biochimie 87, 1005–1010 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Kessler, R., Bleichert, F., Warnke, J. P. & Eschrich, K. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is up-regulated in high-grade astrocytomas. J. Neurooncol. 86, 257–264 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Miller, D. M., Thomas, S. D., Islam, A., Muench, D. & Sedoris, K. c-Myc and cancer metabolism. Clin. Cancer Res. 18, 5546–5553 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hsieh, A. L., Walton, Z. E., Altman, B. J., Stine, Z. E. & Dang, C. V. MYC and metabolism on the path to cancer. Semin. Cell Dev. Biol. 43, 11–21 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Stine, Z. E., Walton, Z. E., Altman, B. J., Hsieh, A. L. & Dang, C. V. MYC metabolism, and cancer. Cancer Discov. 5, 1024–1039 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Berkers, C. R., Maddocks, O. D., Cheung, E. C., Mor, I. & Vousden, K. H. Metabolic regulation by p53 family members. Cell. Metab. 18, 617–633 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Liu, J., Zhang, C., Hu, W. & Feng, Z. Tumor suppressor p53 and its mutants in cancer metabolism. Cancer Lett. 356, 197–203 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Cheung, E. C., Ludwig, R. L. & Vousden, K. H. Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc. Natl Acad. Sci. USA 109, 20491–20496 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhang, C. et al. Tumour-associated mutant p53 drives the Warburg effect. Nat. Commun. 4, 2935 (2013).

    Article  PubMed  CAS  Google Scholar 

  83. Karim, S., Adams, D. H. & Lalor, P. F. Hepatic expression and cellular distribution of the glucose transporter family. World J. Gastroenterol. 18, 6771–6781 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Guzman, G. et al. Evidence for heightened hexokinase II immunoexpression in hepatocyte dysplasia and hepatocellular carcinoma. Dig. Dis. Sci. 60, 420–426 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Castaldo, G. et al. Quantitative analysis of aldolase A mRNA in liver discriminates between hepatocellular carcinoma and cirrhosis. Clin. Chem. 46, 901–906 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Wang, Y. et al. Identification of four isoforms of aldolase B down-regulated in hepatocellular carcinoma tissues by means of two-dimensional western blotting. In Vivo 25, 881–886 (2011).

    CAS  PubMed  Google Scholar 

  87. Penhoet, E. E. & Rutter, W. J. Catalytic and immunochemical properties of homomeric and heteromeric combinations of aldolase subunits. J. Biol. Chem. 246, 318–323 (1971).

    Article  CAS  PubMed  Google Scholar 

  88. Asaka, M. et al. Alteration of aldolase isozymes in serum and tissues of patients with cancer and other diseases. J. Clin. Lab Anal. 8, 144–148 (1994).

    Article  CAS  PubMed  Google Scholar 

  89. Hu, H. et al. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell 164, 433–446 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang, B., Hsu, S. H., Frankel, W., Ghoshal, K. & Jacob, S. T. Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating glucose-6-phosphatase and peroxisome proliferator-activated receptor γ, coactivator 1α. Hepatology 56, 186–197 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Wong, C. C. et al. Switching of pyruvate kinase isoform L to M2 promotes metabolic reprogramming in hepatocarcinogenesis. PLoS ONE 9, e115036 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Pan, D., Mao, C. & Wang, Y. X. Suppression of gluconeogenic gene expression by LSD1-mediated histone demethylation. PLoS ONE 8, e66294 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Massari, F. et al. Metabolic alterations in renal cell carcinoma. Cancer Treat. Rev. 41, 767–776 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Li, B. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251–255 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Mendez-Lucas, A., Hyrossova, P., Novellasdemunt, L., Vinals, F. & Perales, J. C. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) is a pro-survival, endoplasmic reticulum (ER) stress response gene involved in tumor cell adaptation to nutrient availability. J. Biol. Chem. 289, 22090–22102 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Leithner, K. et al. PCK2 activation mediates an adaptive response to glucose depletion in lung cancer. Oncogene 34, 1044–1050 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Vincent, E. E. et al. Mitochondrial phosphoenolpyruvate carboxykinase regulates metabolic adaptation and enables glucose-independent tumor growth. Mol. Cell 60, 195–207 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Montal, E. D. et al. PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth. Mol. Cell 60, 571–583 (2015). References 95–98 showed that the gluconeogenic enzymes, PEPCK-M and PEPCK-C, are expressed in some cancer cells to promote tumour growth when glucose is limited.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Nogueira, V. & Hay, N. Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy. Clin. Cancer Res. 19, 4309–4314 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012). References 100 and 101 showed that extracellular matrix detachment induces energetic and oxidative stress, and AMPK activation. AMPK activation is required to maintain NADPH homeostasis to promote cell survival during extracellular matrix detachment and solid tumour formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Adekola, K., Rosen, S. T. & Shanmugam, M. Glucose transporters in cancer metabolism. Curr. Opin. Oncol. 24, 650–654 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Szablewski, L. Expression of glucose transporters in cancers. Biochim. Biophys. Acta 1835, 164–169 (2013).

    CAS  PubMed  Google Scholar 

  105. Mueckler, M. & Thorens, B. The SLC2 (GLUT) family of membrane transporters. Mol. Aspects Med. 34, 121–138 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. McBrayer, S. K. et al. Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy. Blood 119 4686–4697 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chan, D. A. et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci. Transl Med. 3, 94ra70 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Liu, Y. et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol. Cancer Ther. 11, 1672–1682 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Wang, D. et al. A mouse model for Glut-1 haploinsufficiency. Hum. Mol. Genet. 15, 1169–1179 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Rumsey, S. C. et al. Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid. J. Biol. Chem. 272, 18982–18989 (1997).

    Article  CAS  PubMed  Google Scholar 

  111. Corpe, C. P., Eck, P., Wang, J., Al-Hasani, H. & Levine, M. Intestinal dehydroascorbic acid (DHA) transport mediated by the facilitative sugar transporters, GLUT2 and GLUT8. J. Biol. Chem. 288, 9092–9101 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Uetaki, M., Tabata, S., Nakasuka, F., Soga, T. & Tomita, M. Metabolomic alterations in human cancer cells by vitamin C-induced oxidative stress. Sci. Rep. 5, 13896 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Chen, Q. et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl Acad. Sci. USA 105, 11105–11109 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mikirova, N., Casciari, J., Rogers, A. & Taylor, P. Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J. Transl Med. 10, 189 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Trachootham, D. et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 10, 241–252 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Nogueira, V. et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14, 458–470 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Xu, K. & Thornalley, P. J. Involvement of glutathione metabolism in the cytotoxicity of the phenethyl isothiocyanate and its cysteine conjugate to human leukaemia cells in vitro. Biochem. Pharmacol. 61, 165–177 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Heikkinen, S. et al. Hexokinase II-deficient mice. Prenatal death of homozygotes without disturbances in glucose tolerance in heterozygotes. J. Biol. Chem. 274, 22517–22523 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. Majewski, N. et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell 16, 819–830 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Majewski, N., Nogueira, V., Robey, R. B. & Hay, N. Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol. Cell. Biol. 24, 730–740 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Robey, R. B. & Hay, N. Mitochondrial hexokinases: guardians of the mitochondria. Cell Cycle 4, 654–658 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Clem, B. et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol. Cancer Ther. 7, 110–120 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Clem, B. F. et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol. Cancer Ther. 12, 1461–1470 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Chesney, J., Clark, J., Lanceta, L., Trent, J. O. & Telang, S. Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor. Oncotarget 6, 18001–18011 (2015). References 124 and 125 describe inhibitors of PFKFB3 and PFKFB4 that can be used for cancer therapy.

    Article  PubMed  PubMed Central  Google Scholar 

  126. De Bock, K. et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154, 651–663 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Schoors, S. et al. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell. Metab. 19, 37–48 (2014).

    Article  CAS  PubMed  Google Scholar 

  128. Mullarky, E. et al. Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. Proc. Natl Acad. Sci. USA 113, 1778–1783 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Locasale, J. W. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572–583 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015). References 130 and 131 showed that there is metabolic competition in the microenvironment between tumour-infiltrating T cells and the tumour cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci. Transl Med. 8, 328rv4 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The work is supported by grants CA090764, and AG016927 from the National Institutes of Health and by a Veteran Affairs Merit Award BX000733 to N.H.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nissim Hay.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

PowerPoint slides

Glossary

Aerobic glycolysis

Conversion of glucose into lactate that takes place in the presence of oxygen.

Oxidative phosphorylation

(OXPHO). A metabolic process of nutrient oxidation that generates ATP in mitochondria.

Pentose phosphate pathway

(PPP). A metabolic process in which glucose is used to generate NADPH and ribose-5-phosphate for nucleotide biosynthesis.

Hexosamine pathway

A metabolic process in which an amine group is added to hexoses to generate a sugar donor for the glycosylation of proteins.

One-carbon metabolism

Biochemical reactions catalysed by a set of enzymes and coenzymes in which the transfer of one-carbon groups occurs to provide precursors for purine synthesis and the methionine cycle.

Tricarboxylic acid cycle

(TCA cycle). A series of chemical reactions that start with oxidation of acetyl-CoA to generate precursors for certain amino acids and a reducing agent for oxidative phosphorylation.

Folate cycle

A metabolic pathway, included in one-carbon metabolism, that uses tetrahydrofolates as cofactors and precursors for purine synthesis and the methionine cycle.

Methionine cycle

Part of one-carbon metabolism, the methionine cycle generates S-adenosylmethionine, which is a substrate for methyltransferases.

Hypoglycorrhachia

An abnormally low glucose level in the cerebrospinal fluid.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hay, N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?. Nat Rev Cancer 16, 635–649 (2016). https://doi.org/10.1038/nrc.2016.77

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc.2016.77

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer