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:

Oxygen availability and metabolic adaptations

Nature Reviews Cancer volume 16, pages 663–673 (2016)Cite this article

Subjects

Key Points

  • Tumour microenvironments harbour multiple microdomains whereby cells experience limited (and highly variable) access to oxygen and nutrients.

  • Oxygen and nutrient availability affect tumour evolution via altered metabolism, blood vessel recruitment, inflammatory cell infiltration and metastasis.

  • Although much of hypoxia research has previously focused on hypoxia-inducible factor (HIF) transcriptional regulators, multiple additional O2-sensing mechanisms are at play, including those regulated by mTOR complex 1 (mTORC1), endoplasmic reticulum stress responses, autophagy and numerous oxygen-consuming metabolic pathways.

  • The HIFs, as central regulators of metabolic adaptations in hypoxic tumours, significantly influence intracellular metabolism but are also in turn governed by changes in metabolite accumulation.

  • The human genome encodes up to 70 2-oxoglutarate-dependent dioxygenases that probably contribute to tumour phenotypes at the biosynthetic, metabolic, genetic and epigenetic levels.

Abstract

Oxygen availability, along with the abundance of nutrients (such as glucose, glutamine, lipids and albumin), fluctuates significantly during tumour evolution and the recruitment of blood vessels, leukocytes and reactive fibroblasts to complex tumour microenvironments. As such, hypoxia and concomitant nutrient scarcity affect large gene expression programmes, signalling pathways, diverse metabolic reactions and various stress responses. This Review summarizes our current understanding of how these adaptations are integrated in hypoxic tumour cells and their role in disease progression.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Post-translational regulation of hypoxia-inducible factor-α (HIFα) subunits under normoxic and hypoxic conditions.
Figure 2: Glycolysis, the tricarboxylic acid cycle and lipid synthesis.
Figure 3: The mTORC1 and mTORC2 pathways and their interaction with hypoxia.
Figure 4: The autophagic pathway and its regulators.

Similar content being viewed by others

References

  1. Lee, K. E. & Simon, M. C. SnapShot: hypoxia-inducible factors. Cell 163, 1288 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Qiu, B. & Simon, M. C. Oncogenes strike a balance between cellular growth and homeostasis. Semin. Cell Dev. Biol. 43, 3–10 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ratcliffe, P. J. Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J. Physiol. 591, 2027–2042 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Brizel, D. M. et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 56, 941–943 (1996).

    CAS  PubMed  Google Scholar 

  5. Hockel, M. et al. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother. Oncol. 26, 45–50 (1993). This paper was among the first to directly measure tumour oxygenation in 15 patients undergoing radiotherapy treatment, and demonstrated that pO 2 can be an independent prognostic factor influencing survival in advanced-stage cancer of the uterine cervix.

    Article  CAS  PubMed  Google Scholar 

  6. Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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 

  8. Semenza, G. L. et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem. 271, 32529–32537 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Iyer, N. V. et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 12, 149–162 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gordan, J. D., Thompson, C. B. & Simon, M. C. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12, 108–113 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187–197 (2006). References 11 and 12 demonstrated that the HIF1α target PDK1, which inactivates PDH, results in a hypoxia-induced metabolic switch that shunts glucose metabolites away from the mitochondria to glycolysis, to maintain ATP production and prevent toxic ROS build-up.

    Article  CAS  PubMed  Google Scholar 

  13. Guzy, R. D. et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab. 1, 401–408 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Mansfield, K. D. et al. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab. 1, 393–399 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chandel, N. S. et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia: a mechanism of O2 sensing. J. Biol. Chem. 275, 25130–25138 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Lee, G. et al. Oxidative dimerization of PHD2 is responsible for its inactivation and contributes to metabolic reprogramming via HIF-1α activation. Sci. Rep. 6, 18928 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dupuy, F. et al. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab. 22, 577–589 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. 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 

  19. Fukuda, R. et al. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129, 111–122 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Tello, D. et al. Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting Complex I activity. Cell Metab. 14, 768–779 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Hervouet, E. et al. A new role for the von Hippel–Lindau tumor suppressor protein: stimulation of mitochondrial oxidative phosphorylation complex biogenesis. Carcinogenesis 26, 531–539 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, H. et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11, 407–420 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Walter, K. M. et al. Hif-2α promotes degradation of mammalian peroxisomes by selective autophagy. Cell Metab. 20, 882–897 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Rao, X. et al. O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth. Nat. Commun. 6, 8468 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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  PubMed  PubMed Central  Google Scholar 

  27. Favaro, E. et al. Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab. 16, 751–764 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Luo, W. et al. Pyruvate kinase M2 Is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145, 732–744 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Palsson-McDermott, E. M. et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1beta induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 21, 65–80 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yang, W. et al. EGFR-induced and PKCepsilon monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol. Cell 48, 771–784 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jiang, Y. et al. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol. Cell 53, 75–87 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Jiang, Y. et al. PKM2 phosphorylates MLC2 and regulates cytokinesis of tumour cells. Nat. Commun. 5, 5566 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Israelsen, W. J. et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155, 397–409 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Li, B. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251–255 (2014). This paper describes a prominent metabolic enzyme that has both catalytic and structural roles in regulating both intracellular metabolism and nuclear transcription factor activity; other enzymes such as PKM2 and argininosuccinate synthase 1 (ASS1) represent additional examples of enzymes with key adaptor protein functions beyond their traditional enzymatic functions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pollard, P. J., Wortham, N. C. & Tomlinson, I. P. The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase. Ann. Med. 35, 632–639 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30, 406–410 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Isaacs, J. S. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143–153 (2005). References 37 and 38 describe how TCA cycle intermediates such as succinate and fumarate, represent a mitochondrion to cytosol signalling pathway that links mitochondrial dysfunction downstream of mutations in enzymes, such as SDH and FH, to inhibit the PHD-mediated turnover of HIF1α.

    Article  CAS  PubMed  Google Scholar 

  39. Koivunen, P. et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 282, 4524–4532 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Masson, N., William, C., Maxwell, P. H., Pugh, C. W. & Ratcliffe, P. J. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 20, 5197–5206 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Markolovic, S., Wilkins, S. E. & Schofield, C. J. Protein hydroxylation catalyzed by 2-oxoglutarate-dependent oxygenases. J. Biol. Chem. 290, 20712–20722 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Laukka, T. et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256–4265 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010). Ward et al . demonstrate that a shared feature of cancer-associated IDH mutations is the production of extremely high levels of the oncometabolite 2HG.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Koivunen, P. et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484–488 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tarhonskaya, H. et al. Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases. Nat. Commun. 5, 3423 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Nytko, K. J. et al. Vitamin C is dispensable for oxygen sensing in vivo. Blood 117, 5485–5493 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Knowles, H. J., Raval, R. R., Harris, A. L. & Ratcliffe, P. J. Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. Cancer Res. 63, 1764–1768 (2003).

    CAS  PubMed  Google Scholar 

  50. Knowles, H. J., Mole, D. R., Ratcliffe, P. J. & Harris, A. L. Normoxic stabilization of hypoxia-inducible factor-1alpha by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1. Cancer Res. 66, 2600–2607 CAN-05-2351 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Kuiper, C., Dachs, G. U., Currie, M. J. & Vissers, M. C. Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. Free Radic. Biol. Med. 69, 308–317 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Kuiper, C. et al. Increased tumor ascorbate is associated with extended disease-free survival and decreased hypoxia-inducible factor-1 activation in human colorectal cancer. Front. Oncol. 4, 10 (2014).

    PubMed  PubMed Central  Google Scholar 

  53. Ramakrishnan, S. K. & Shah, Y. M. Role of intestinal HIF-2α in health and disease. Annu. Rev. Physiol. 78, 301–325 (2016).

    Article  CAS  PubMed  Google Scholar 

  54. Mastrogiannaki, M., Matak, P. & Peyssonnaux, C. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. Blood 122, 885–892 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zimmer, M. et al. Small-molecule inhibitors of HIF-2a translation link its 5′UTR iron-responsive element to oxygen sensing. Mol. Cell 32, 838–848 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gruber, M. et al. Acute postnatal ablation of Hif-2α results in anemia. Proc. Natl Acad. Sci. USA 104, 2301–2306 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rankin, E. B. et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J. Clin. Invest. 117, 1068–1077 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-keto-glutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012).

    Article  CAS  Google Scholar 

  60. Mullen, A. R. et al. Oxidation of α-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep. 7, 1679–1690 (2014). References 58–60 demonstrate that hypoxia and mutations in key TCA cycle enzymes result in reductive carboxylation of 2OG, which can support lipid homeostasis, especially downstream of glutamine catabolism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sun, R. C. & Denko, N. C. Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab. 19, 285–292 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Schug, Z. T. et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27, 57–71 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591–1602 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603–1614 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ackerman, D. & Simon, M. C. Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol. 24, 472–478 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zaidi, N. et al. Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog. Lipid Res. 52, 585–589 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7, 763–777 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Kuemmerle, N. B. et al. Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Mol. Cancer Ther. 10, 427–436 MCT-10-0802 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Young, R. M. et al. Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. Genes Dev. 27, 1115–1131 (2013). This was one of the first papers to show that a fundamental biosynthetic reaction, that is, fatty acid desaturation, can be inhibited by pO 2 levels typical of hypoxic microdomains detected in solid tumours.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wang, D., Wei, Y. & Pagliassotti, M. J. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 147, 943–951 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Kamphorst, J. J. et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc. Natl Acad. Sci. USA 110, 8882–8887 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Qiu, B. et al. HIF-2α dependent lipid storage promotes endoplasmic reticulum homeostasis in clear cell renal cell carcinoma. Cancer Discov. 5, 652–657 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bensaad, K. et al. Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep. 9, 349–365 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chowdhury, R. et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463–469 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Losman, J. A. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621–1625 (2013). References 76–78 convincingly demonstrate that the oncometabolite 2HG affects the epigenome via histone methylation status.

    Article  CAS  PubMed  Google Scholar 

  79. Intlekofer, A. M. et al. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab. 22, 304–311 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Oldham, W. M., Clish, C. B., Yang, Y. & Loscalzo, J. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 22, 291–303 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Harris, A. L. A. New hydroxy metabolite of 2-oxoglutarate regulates metabolism in hypoxia. Cell Metab. 22, 198–200 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Shim, E. H. et al. L-2-hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 4, 1290–1298 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lee, D. C. et al. A lactate-induced response to hypoxia. Cell 161, 595–609 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Loenarz, C. & Schofield, C. J. Expanding chemical biology of 2-oxoglutarate oxygenases. Nat. Chem. Biol. 4, 152–156 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Hirsila, M. et al. Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway. FASEB J. 19, 1308–1310 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Koivunen, P., Hirsila, M., Kivirikko, K. I. & Myllyharju, J. The length of peptide substrates has a marked effect on hydroxylation by the hypoxia-inducible factor prolyl 4-hydroxylases. J. Biol. Chem. 281, 28712–28720 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Hewitson, K. S. et al. Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates. J. Biol. Chem. 282, 3293–3301 (2007).

    CAS  PubMed  Google Scholar 

  88. Pan, Y. et al. Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Mol. Cell. Biol. 27, 912–925 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liu, L. et al. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol. Cell 21, 521–531 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R. & Kaelin, W. G. Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4, 147–158 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Faubert, B. et al. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α. Proc. Natl Acad. Sci. USA 111, 2554–2559 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Reiling, J. H. & Hafen, E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev. 18, 2879–2892 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Corradetti, M. N., Inoki, K. & Guan, K. L. The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. J. Biol. Chem. 280, 9769–9772 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Miyazaki, M. & Esser, K. A. REDD2 is enriched in skeletal muscle and inhibits mTOR signaling in response to leucine and stretch. Am. J. Physiol. Cell Physiol. 296, C583–592 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Elorza, A. et al. HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol. Cell 48, 681–691 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Keith, B., Johnson, R. S. & Simon, M. C. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12, 9–22 (2012).

    Article  CAS  Google Scholar 

  101. Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935–945 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gulati, P. et al. Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab. 7, 456–465 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Chen, S. et al. CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death. J. Neurochem. 119, 1108–1118 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Nakazawa, M. S. et al. Epigenetic re-expression of HIF-2α suppresses soft tissue sarcoma growth. Nat. Commun. 7, 10539 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nat. Rev. Cancer 7, 961–967 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Morselli, E. et al. Anti- and pro-tumor functions of autophagy. Biochim. Biophys. Acta 1793, 1524–1532 (2009).

    Article  CAS  PubMed  Google Scholar 

  109. Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Rouschop, K. M. et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J. Clin. Invest. 120, 127–141 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Maiuri, M. C., Zalckvar, E., Kimchi, A. & Kroemer, G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 8, 741–752 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Rubinsztein, D. C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709–730 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gupta, A. et al. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc. Natl Acad. Sci. USA 107, 14333–14338 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Yamamoto, A. et al. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct. Funct. 23, 33–42 (1998).

    Article  CAS  PubMed  Google Scholar 

  116. Bellot, G. et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol. Cell. Biol. 29, 2570–2581 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bertout, J. A., Patel, S. A. & Simon, M. C. The impact of O2 availability on human cancer. Nat. Rev. Cancer 8, 967–975 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Semenza, G. L. HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr. Pharm. Des. 15, 3839–3843 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Scheuermann, T. H. et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat. Chem. Biol. 9, 271–276 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wu, D., Potluri, N., Lu, J., Kim, Y. & Rastinejad, F. Structural integration in hypoxia-inducible factors. Nature 524, 303–308 (2015). This paper describes crystal structures for each of the HIF1α–ARNT and HIF2α–ARNT heterodimers in states that include bound small molecules and HRE DNA.

    Article  CAS  PubMed  Google Scholar 

  121. Pourmorteza, M., Rahman, Z. U. & Young, M. Evofosfamide, a new horizon in the treatment of pancreatic cancer. Anticancer Drugs 27, 723–725 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Lohse, I. et al. Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302. Oncotarget http://dx.doi.org/10.18632/oncotarget.9654 (2016).

  123. Zhang, X. et al. MR imaging biomarkers to monitor early response to hypoxia-activated prodrug TH-302 in pancreatic cancer xenografts. PLoS ONE 11, e0155289 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to specifically thank F. Tucker for her assistance in preparing the manuscript. M.S.N.'s research is supported by the US National Cancer Institute (NCI) R01 CA158301; B.K. and M.C.S acknowledge support from NCI P01 CA104838.

Author information

Authors and Affiliations

  1. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania,

    Michael S. Nakazawa, Brian Keith & M. Celeste Simon

  2. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania,

    Michael S. Nakazawa & Brian Keith

  3. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, 456 BRB II/III, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    M. Celeste Simon

Authors
  1. Michael S. Nakazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian Keith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Celeste Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael S. Nakazawa.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Ischaemic conditions

Tissue environment in which cells are limited for oxygen and other blood-borne nutrients (such as glucose, glutamine, lipids and albumin) simultaneously, as opposed to being merely O2 deprived or hypoxic.

Glycolysis

Central carbon metabolic pathway in which glucose is catabolized to lactate and/or pyruvate.

Redox stress

Pathological setting in which cells and tissues experience an imbalance in oxidant versus antioxidant agents.

Reactive oxygen species

(ROS). Oxygen-containing molecules harbouring an additional unpaired electron; for example, H2O2, OH− and O2−.

Mitophagy

A specialized form of autophagy devoted to breakdown of mitochondria in response to certain stimuli.

Gluconeogenesis

The reverse pathway in central carbon metabolism (relative to glycolysis) in which glucose is generated from precursors, and maintained as free glucose or converted into storage depots such as glycogen.

Anaplerosis

An intracellular process whereby tricarboxylic acid (TCA) cycle intermediates are replenished when they become limiting; for example, when entry of glucose-derived carbons is insufficient to maintain the mitochondrial TCA cycle, glutamine-derived carbons can replenish the pathway, maintaining homeostasis.

Phytanic acid

3,7,11,15-tetramethylhexadecanoic acid, a branched-chain fatty acid that humans obtain via consumption of, for example, diary products, beef and fish.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakazawa, M., Keith, B. & Simon, M. Oxygen availability and metabolic adaptations. Nat Rev Cancer 16, 663–673 (2016). https://doi.org/10.1038/nrc.2016.84

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc.2016.84

This article is cited by

Search

Advanced 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