Skip to main content

Advertisement

SpringerLink
Log in

Effects of hypoxia on tumor metabolism

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Rapidly growing tumors invariably contain hypoxic regions. Adaptive response to hypoxia through angiogenesis, enhanced glucose metabolism and diminished but optimized mitochondrial respiration confers survival and growth advantage to hypoxic tumor cells. In this review, the roles of hypoxia, the hypoxia inducible factors, oncogenes and tumor suppressors in metabolic adaptation of tumors are discussed. These new insights into hypoxic metabolic alterations in tumors will hopefully lead us to target tumor bioenergetics for the treatment of cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hochachka, P. W. (1998). Mechanism and evolution of hypoxia-tolerance in humans. Journal of Experimental Biology, 201, 1243–1254.

    PubMed  CAS  Google Scholar 

  2. Semenza, G. L. (1999). Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annual Review of Cell and Developmental Biology, 15, 551–578.

    PubMed  CAS  Google Scholar 

  3. Giatromanolaki, A., & Harris, A. L. (2001). Tumour hypoxia, hypoxia signaling pathways and hypoxia inducible factor expression in human cancer. Anticancer Research, 21, 4317–4324.

    PubMed  CAS  Google Scholar 

  4. Semenza, G. L. (2000). Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Critical Reviews in Biochemistry and Molecular Biology, 35, 71–103.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  6. Wang, G. L., & Semenza, G. L. (1993). General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 90, 4304–4308.

    PubMed  CAS  Google Scholar 

  7. Forsythe, J. A., Jiang, B. H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., et al. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Molecular and cellular biology, 16, 4604–4613.

    PubMed  CAS  Google Scholar 

  8. Gordan, J. D., & Simon, M. C. (2007). Hypoxia-inducible factors: Central regulators of the tumor phenotype. Current Opinion in Genetics & Development, 17, 71–77.

    CAS  Google Scholar 

  9. Semenza, G. L. (2001). HIF-1, O(2), and the 3 PHDs: How animal cells signal hypoxia to the nucleus. Cell, 107, 1–3.

    PubMed  CAS  Google Scholar 

  10. Semenza, G. L. (2004). Hydroxylation of HIF-1: Oxygen sensing at the molecular level. Physiology (Bethesda), 19, 176–182.

    CAS  Google Scholar 

  11. Schofield, C. J., & Ratcliffe, P. J. (2004). Oxygen sensing by HIF hydroxylases. Nature Reviews. Molecular Cell Biology, 5, 343–354.

    PubMed  CAS  Google Scholar 

  12. Krek, W. (2000). VHL takes HIF’s breath away. Nature Cell Biology, 2, E121–E123.

    PubMed  CAS  Google Scholar 

  13. Jaakkola, P., Mole, D. R., Tian, Y. M., Wilson, M. I., Gielbert, J., Gaskell, S. J., et al. (2001). Targeting of HIF-alpha to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292, 468–472.

    PubMed  CAS  Google Scholar 

  14. Ohh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T. Y., Huang, L. E., et al. (2000). Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel–Lindau protein. Nature Cell Biology, 2, 423–427.

    PubMed  CAS  Google Scholar 

  15. Carmeliet, P., Dor, Y., Herbert, J. M., Fukumura, D., Brusselmans, K., Dewerchin, M., et al. (1998). Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature, 394, 485–490.

    PubMed  CAS  Google Scholar 

  16. Liu, L., & Simon, M. C. (2004). Regulation of transcription and translation by hypoxia. Cancer Biology & Therapy, 3, 492–497.

    Article  CAS  Google Scholar 

  17. Semenza, G. L. (2003). Targeting HIF-1 for cancer therapy. Nature Reviews Cancer, 3, 721–732.

    PubMed  CAS  Google Scholar 

  18. Ryan, H. E., Lo, J., & Johnson, R. S. (1998). HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO Journal, 17, 3005–3015.

    PubMed  CAS  Google Scholar 

  19. Fei, P., Wang, W., Kim, S. H., Wang, S., Burns, T. F., Sax, J. K., et al. (2004). Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth. Cancer Cell, 6, 597–609.

    PubMed  CAS  Google Scholar 

  20. Hammond, E. M., & Giaccia, A. J. (2005). The role of p53 in hypoxia-induced apoptosis. Biochemical and Biophysical Research Communications, 331, 718–725.

    PubMed  CAS  Google Scholar 

  21. Kim, J. W., & Dang, C. V. (2006). Cancer’s molecular sweet tooth and the Warburg effect. Cancer Research, 66, 8927–8930.

    PubMed  CAS  Google Scholar 

  22. Bardos, J. I., & Ashcroft, M. (2004). Hypoxia-inducible factor-1 and oncogenic signalling. Bioessays, 26, 262–269.

    PubMed  CAS  Google Scholar 

  23. Semenza, G. L., Shimoda, L. A., & Prabhakar, N. R. (2006). Regulation of gene expression by HIF-1. Novartis Foundation symposium, 272, 2–8; discussion 8–14, 33–36.

    PubMed  CAS  Google Scholar 

  24. Semenza, G. L., Jiang, B. H., Leung, S. W., Passantino, R., Concordet, J. P., Maire, P., et al. (1996). Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. Journal of Biological Chemistry, 271, 32529–32537.

    PubMed  CAS  Google Scholar 

  25. Fantin, V. R., St-Pierre, J., & Leder, P. (2006). Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell, 9, 425–434.

    PubMed  CAS  Google Scholar 

  26. Balaban, R. S., Nemoto, S., & Finkel, T. (2005). Mitochondria, oxidants, and aging. Cell, 120, 483–495.

    PubMed  CAS  Google Scholar 

  27. Kondoh, H., Lleonart, M. E., Gil, J., Wang, J., Degan, P., Peters, G., et al. (2005). Glycolytic enzymes can modulate cellular life span. Cancer Research, 65, 177–185.

    PubMed  CAS  Google Scholar 

  28. Welford, S. M., Bedogni, B., Gradin, K., Poellinger, L., Broome Powell, M., & Giaccia, A. J. (2006). HIF1alpha delays premature senescence through the activation of MIF. Genes & Development, 20, 3366–3371.

    CAS  Google Scholar 

  29. Maity, A., & Koumenis, C. (2006). HIF and MIF-a nifty way to delay senescence? Genes & development, 20, 3337–3341.

    CAS  Google Scholar 

  30. Kaelin, W. G. (2005). ROS: Really involved in oxygen sensing. Cell Metabolism, 1, 357–358.

    PubMed  CAS  Google Scholar 

  31. Guzy, R. D., Hoyos, B., Robin, E., Chen, H., Liu, L., Mansfield, K. D., et al. (2005). Mitochondrial complex III is required for hypoxia-induced ROS and cellular oxygen sensing. Cell Metabolism, 1, 401–408.

    PubMed  CAS  Google Scholar 

  32. Brunelle, J. K., Bell, E. L., Quesada, N. M., Vercauteren, K., Tiranti, V., Zeviani, M., et al. (2005). Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metabolism, 1, 409–414.

    PubMed  CAS  Google Scholar 

  33. Cairns, R., Papandreou, I., & Denko, N. (2006). Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment. Molecular Cancer Research, 4, 61–70.

    PubMed  CAS  Google Scholar 

  34. Bacon, A. L., & Harris, A. L. (2004). Hypoxia-inducible factors and hypoxic cell death in tumour physiology. Annals of Medicine, 36, 530–539.

    PubMed  CAS  Google Scholar 

  35. Wykoff, C. C., Beasley, N. J., Watson, P. H., Turner, K. J., Pastorek, J., Sibtain, A., et al. (2000). Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Research, 60, 7075–7083.

    PubMed  CAS  Google Scholar 

  36. Svastova, E., Hulikova, A., Rafajova, M., Zat’ovicova, M., Gibadulinova, A., Casini, A., et al. (2004). Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS letters, 577, 439–445.

    PubMed  CAS  Google Scholar 

  37. Robertson, N., Potter, C., & Harris, A. L. (2004). Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Research, 64, 6160–6165.

    PubMed  CAS  Google Scholar 

  38. Potter, C., & Harris, A. L. (2004). Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle, 3, 164–167.

    PubMed  CAS  Google Scholar 

  39. Supuran, C. T., Scozzafava, A., & Casini, A. (2003). Carbonic anhydrase inhibitors. Medicinal Research Reviews, 23, 146–189.

    PubMed  CAS  Google Scholar 

  40. Potter, C. P., & Harris, A. L. (2003). Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer. British Journal of Cancer, 89, 2–7.

    PubMed  CAS  Google Scholar 

  41. Holness, M. J., & Sugden, M. C. (2003). Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochemical Society Transactions, 31, 1143–1151.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  43. Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L., & Denko, N. C. (2006). HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metabolism, 3, 187–197.

    PubMed  CAS  Google Scholar 

  44. Koukourakis, M. I., Giatromanolaki, A., Sivridis, E., Gatter, K. C., & Harris, A. L. (2005). Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma. Neoplasia, 7, 1–6.

    PubMed  CAS  Google Scholar 

  45. Fukuda, R., Zhang, H., Kim, J. W., Shimoda, L., Dang, C. V., & Semenza, G. L. (2007). HIF-1 regulates cytochrome oxidase subunit composition to optimize the efficiency of respiration in hypoxic cells. Cell, (in press).

  46. Poyton, R. O. (1999). Models for oxygen sensing in yeast: Implications for oxygen-regulated gene expression in higher eucaryotes. Respiration Physiology, 115, 119–133.

    PubMed  CAS  Google Scholar 

  47. Burke, P. V., & Poyton, R. O. (1998). Structure/function of oxygen-regulated isoforms in cytochrome c oxidase. Journal of Experimental Biology, 201, 1163–1175.

    PubMed  CAS  Google Scholar 

  48. Kwast, K. E., Burke, P. V., & Poyton, R. O. (1998). Oxygen sensing and the transcriptional regulation of oxygen-responsive genes in yeast. Journal of Experimental Biology, 201, 1177–1195.

    PubMed  CAS  Google Scholar 

  49. Tian, H., McKnight, S. L., & Russell, D. W. (1997). Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes & Development, 11, 72–82.

    CAS  Google Scholar 

  50. Card, P. B., Erbel, P. J., & Gardner, K. H. (2005). Structural basis of ARNT PAS-B dimerization: Use of a common beta-sheet interface for hetero- and homodimerization. Journal of Molecular Biology, 353, 664–677.

    PubMed  CAS  Google Scholar 

  51. Appelhoff, R. J., Tian, Y. M., Raval, R. R., Turley, H., Harris, A. L., Pugh, C. W., et al. (2004). Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. Journal of Biological Chemistry, 279, 38458–38465.

    PubMed  CAS  Google Scholar 

  52. Hu, C. J., Wang, L. Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003). Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Molecular and Cellular Biology, 23, 9361–9374.

    PubMed  CAS  Google Scholar 

  53. Warnecke, C., Zaborowska, Z., Kurreck, J., Erdmann, V. A., Frei, U., Wiesener, M., et al. (2004). Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: Erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. FASEB Journal, 18, 1462–1464.

    PubMed  CAS  Google Scholar 

  54. Covello, K. L., Kehler, J., Yu, H., Gordan, J. D., Arsham, A. M., Hu, C. J., et al. (2006). HIF-2alpha regulates Oct-4: Effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes & Development, 20, 557–570.

    CAS  Google Scholar 

  55. Aprelikova, O., Wood, M., Tackett, S., Chandramouli, G. V., & Barrett, J. C. (2006). Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection. Cancer Research, 66, 5641–5647.

    PubMed  CAS  Google Scholar 

  56. Maranchie, J. K., & Zhan, Y. (2005). Nox4 is critical for hypoxia-inducible factor 2-alpha transcriptional activity in von Hippel–Lindau-deficient renal cell carcinoma. Cancer Research, 65, 9190–9193.

    PubMed  CAS  Google Scholar 

  57. Seagroves, T., & Johnson, R. S. (2002). Two HIFs may be better than one. Cancer Cell, 1, 211–213.

    PubMed  CAS  Google Scholar 

  58. Acker, T., Diez-Juan, A., Aragones, J., Tjwa, M., Brusselmans, K., Moons, L., et al. (2005). Genetic evidence for a tumor suppressor role of HIF-2alpha. Cancer Cell, 8, 131–141.

    PubMed  CAS  Google Scholar 

  59. Covello, K. L., Simon, M. C., & Keith, B. (2005). Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Cancer Research, 65, 2277–2286.

    PubMed  CAS  Google Scholar 

  60. Kim, W. Y., Safran, M., Buckley, M. R., Ebert, B. L., Glickman, J., Bosenberg, M., et al. (2006). Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo. EMBO Journal, 25, 4650–4662.

    PubMed  CAS  Google Scholar 

  61. Sowter, H. M., Raval, R. R., Moore, J. W., Ratcliffe, P. J., & Harris, A. L. (2003). Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Research, 63, 6130–6134.

    PubMed  CAS  Google Scholar 

  62. Kuhajda, F. P. (2006). Fatty acid synthase and cancer: New application of an old pathway. Cancer Research, 66, 5977–5980.

    PubMed  CAS  Google Scholar 

  63. Menendez, J. A., Vellon, L., Oza, B. P., & Lupu, R. (2005). Does endogenous fatty acid metabolism allow cancer cells to sense hypoxia and mediate hypoxic vasodilatation? Characterization of a novel molecular connection between fatty acid synthase (FAS) and hypoxia-inducible factor-1alpha (HIF-1alpha)-related expression of vascular endothelial growth factor (VEGF) in cancer cells overexpressing her-2/neu oncogene. Journal of Cellular Biochemistry, 94, 857–863.

    PubMed  CAS  Google Scholar 

  64. Menendez, J. A., Decker, J. P., & Lupu, R. (2005). In support of fatty acid synthase (FAS) as a metabolic oncogene: Extracellular acidosis acts in an epigenetic fashion activating FAS gene expression in cancer cells. Journal of Cellular Biochemistry, 94, 1–4.

    PubMed  CAS  Google Scholar 

  65. Baron, A., Migita, T., Tang, D., & Loda, M. (2004). Fatty acid synthase: A metabolic oncogene in prostate cancer? Journal of Cellular Biochemistry, 91, 47–53.

    PubMed  CAS  Google Scholar 

  66. Pizer, E. S., Wood, F. D., Heine, H. S., Romantsev, F. E., Pasternack, G. R., & Kuhajda, F. P. (1996). Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Research, 56, 1189–1193.

    PubMed  CAS  Google Scholar 

  67. Pizer, E. S., Jackisch, C., Wood, F. D., Pasternack, G. R., Davidson, N. E., & Kuhajda, F. P. (1996). Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Research, 56, 2745–2747.

    PubMed  CAS  Google Scholar 

  68. Alli, P. M., Pinn, M. L., Jaffee, E. M., McFadden, J. M., & Kuhajda, F. P. (2005). Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene, 24, 39–46.

    PubMed  CAS  Google Scholar 

  69. Plas, D. R., & Thompson, C. B. (2005). Akt-dependent transformation: There is more to growth than just surviving. Oncogene, 24, 7435–7442.

    PubMed  CAS  Google Scholar 

  70. Gottlieb, E., & Thompson, C. B. (2003). Targeting the mitochondria to enhance tumor suppression. Methods in Molecular Biology, 223, 543–554.

    PubMed  CAS  Google Scholar 

  71. Bui, T., & Thompson, C. B. (2006). Cancer’s sweet tooth. Cancer Cell, 9, 419–420.

    PubMed  CAS  Google Scholar 

  72. Elstrom, R. L., Bauer, D. E., Buzzai, M., Karnauskas, R., Harris, M. H., Plas, D. R., et al. (2004). Akt stimulates aerobic glycolysis in cancer cells. Cancer Research, 64, 3892–3899.

    PubMed  CAS  Google Scholar 

  73. Li, F., Wang, Y., Zeller, K. I., Potter, J. J., Wonsey, D. R., O’Donnell, K. A., et al. (2005). Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Molecular and Cellular Biology, 25, 6225–6234.

    PubMed  CAS  Google Scholar 

  74. Hatzivassiliou, G., Zhao, F., Bauer, D. E., Andreadis, C., Shaw, A. N., Dhanak, D., et al. (2005). ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell, 8, 311–321.

    PubMed  CAS  Google Scholar 

  75. Bauer, D. E., Hatzivassiliou, G., Zhao, F., Andreadis, C., & Thompson, C. B. (2005). ATP citrate lyase is an important component of cell growth and transformation. Oncogene, 24, 6314–6322.

    PubMed  CAS  Google Scholar 

  76. Pugh, C. W., & Ratcliffe, P. J. (2003). The von Hippel–Lindau tumor suppressor, hypoxia-inducible factor-1 (HIF-1). degradation, and cancer pathogenesis. Seminars in Cancer Biology, 13, 83–89.

    PubMed  CAS  Google Scholar 

  77. Kaelin, W. G., Jr. (2002). Molecular basis of the VHL hereditary cancer syndrome. Nature Reviews Cancer, 2, 673–682.

    PubMed  CAS  Google Scholar 

  78. Clifford, S. C., & Maher, E. R. (2001). Von Hippel–Lindau disease: clinical and molecular perspectives. Advances in Cancer Research, 82, 85–105.

    Article  PubMed  CAS  Google Scholar 

  79. Zelzer, E., Levy, Y., Kahana, C., Shilo, B. Z., Rubinstein, M., & Cohen, B. (1998). Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO Journal, 17, 5085–5094.

    PubMed  CAS  Google Scholar 

  80. Jiang, B. H., Agani, F., Passaniti, A., & Semenza, G. L. (1997). 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 Research, 57, 5328–5335.

    PubMed  CAS  Google Scholar 

  81. Karni, R., Dor, Y., Keshet, E., Meyuhas, O., & Levitzki, A. (2002). Activated pp60c-Src leads to elevated hypoxia-inducible factor (HIF)-1alpha expression under normoxia. Journal of Biological Chemistry, 277, 42919–42925.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  83. Jiang, B. H., Jiang, G., Zheng, J. Z., Lu, Z., Hunter, T., & Vogt, P. K. (2001). Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth & Differentiation, 12, 363–369.

    CAS  Google Scholar 

  84. Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C., & Semenza, G. L. (2001). HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: Novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Molecular and Cellular Biology, 21, 3995–4004.

    PubMed  CAS  Google Scholar 

  85. Brugarolas, J., & Kaelin, W. G., Jr. (2004). Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell, 6, 7–10.

    PubMed  CAS  Google Scholar 

  86. Brugarolas, J., Lei, K., Hurley, R. L., Manning, B. D., Reiling, J. H., Hafen, E., et al. (2004). Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes & Development, 18, 2893–2904.

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  88. Gottlieb, E., & Tomlinson, I. P. (2005). Mitochondrial tumour suppressors: A genetic and biochemical update. Nature Reviews. Cancer, 5, 857–866.

    PubMed  CAS  Google Scholar 

  89. Astuti, D., Latif, F., Dallol, A., Dahia, P. L., Douglas, F., George, E., et al. (2001). Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. American Journal of Human Genetics, 69, 49–54.

    PubMed  CAS  Google Scholar 

  90. Gimm, O., Armanios, M., Dziema, H., Neumann, H. P., & Eng, C. (2000). Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer Research, 60, 6822–6825.

    PubMed  CAS  Google Scholar 

  91. Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., et al. (2000). Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science, 287, 848–851.

    PubMed  CAS  Google Scholar 

  92. Eng, C., Kiuru, M., Fernandez, M. J., & Aaltonen, L. A. (2003). A role for mitochondrial enzymes in inherited neoplasia and beyond. Nature Reviews. Cancer, 3, 193–202.

    PubMed  CAS  Google Scholar 

  93. Brandon, M., Baldi, P., & Wallace, D. C. (2006). Mitochondrial mutations in cancer. Oncogene, 25, 4647–4662.

    PubMed  CAS  Google Scholar 

  94. Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., et al. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell, 7, 77–85.

    PubMed  CAS  Google Scholar 

  95. Gatenby, R. A., & Gillies, R. J. (2004). Why do cancers have high aerobic glycolysis? Nature Reviews. Cancer, 4, 891–899.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  98. Shim, H., Dolde, C., Lewis, B. C., Wu, C. S., Dang, G., Jungmann, R. A., et al. (1997). c-Myc transactivation of LDH-A: Implications for tumor metabolism and growth. Proceedings of the National Academy of Sciences of the United States of America, 94, 6658–6663.

    PubMed  CAS  Google Scholar 

  99. Osthus, R. C., Shim, H., Kim, S., Li, Q., Reddy, R., Mukherjee, M., et al. (2000). Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. Journal of Biological Chemistry, 275, 21797–21800.

    PubMed  CAS  Google Scholar 

  100. Kim, J. W., Zeller, K. I., Wang, Y., Jegga, A. G., Aronow, B. J., O’Donnell, K. A., et al. (2004). Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Molecular and Cellular Biology, 24, 5923–5936.

    PubMed  CAS  Google Scholar 

  101. Rathmell, J. C., Fox, C. J., Plas, D. R., Hammerman, P. S., Cinalli, R. M., & Thompson, C. B. (2003). Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Molecular and Cellular Biology, 23, 7315–7328.

    PubMed  CAS  Google Scholar 

  102. Gottlob, K., Majewski, N., Kennedy, S., Kandel, E., Robey, R. B., & Hay, N. (2001). Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes & Development, 15, 1406–1418.

    CAS  Google Scholar 

  103. Majewski, N., Nogueira, V., Robey, R. B., & Hay, N. (2004). Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Molecular and Cellular Biology, 24, 730–740.

    PubMed  CAS  Google Scholar 

  104. Plas, D. R., Talapatra, S., Edinger, A. L., Rathmell, J. C., & Thompson, C. B. (2001). Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. Journal of Biological Chemistry, 276, 12041–12048.

    PubMed  CAS  Google Scholar 

  105. Corcoran, C. A., Huang, Y., & Sheikh, M. S. (2006). The regulation of energy generating metabolic pathways by p53. Cancer Biology & Therapy, 5, 1610–1613.

    Google Scholar 

  106. Bensaad, K., Tsuruta, A., Selak, M. A., Vidal, M. N., Nakano, K., Bartrons, R., et al. (2006). TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell, 126, 107–120.

    PubMed  CAS  Google Scholar 

  107. Green, D. R., & Chipuk, J. E. (2006). p53 and metabolism: Inside the TIGAR. Cell, 126, 30–32.

    PubMed  CAS  Google Scholar 

  108. Kruse, J. P., & Gu, W. (2006). p53 aerobics: The major tumor suppressor fuels your workout. Cell Metabolism, 4, 1–3.

    PubMed  CAS  Google Scholar 

  109. Assaily, W., & Benchimol, S. (2006). Differential utilization of two ATP-generating pathways is regulated by p53. Cancer Cell, 10, 4–6.

    PubMed  CAS  Google Scholar 

  110. Matoba, S., Kang, J. G., Patino, W. D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P. J., Bunz, F., & Hwang, P. M. (2006). p53 regulates mitochondrial respiration. Science, 312, 1650–1653.

    Google Scholar 

  111. Rider, M. H., Bertrand, L., Vertommen, D., Michels, P. A., Rousseau, G. G., & Hue, L. (2004). 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: Head-to-head with a bifunctional enzyme that controls glycolysis. Biochemical Journal, 381, 561–579.

    PubMed  CAS  Google Scholar 

  112. Perez, J. X., Roig, T., Manzano, A., Dalmau, M., Boada, J., Ventura, F., et al. (2000). Overexpression of fructose 2,6-bisphosphatase decreases glycolysis and delays cell cycle progression. American Journal of Physiology Cell Physiology, 279, C1359–C1365.

    PubMed  CAS  Google Scholar 

  113. Gatenby, R. A., & Gawlinski, E. T. (2003). The glycolytic phenotype in carcinogenesis and tumor invasion: Insights through mathematical models. Cancer Research, 63, 3847–3854.

    PubMed  CAS  Google Scholar 

  114. Mandelkern, M., & Raines, J. (2002). Positron emission tomography in cancer research and treatment. Technology in Cancer Research & Treatment, 1, 423–439.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Jung-whan Kim, Ping Gao & Chi V. Dang

  2. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Chi V. Dang

  3. Ross Research Building, Room 1032, 720 Rutland Avenue, Baltimore, MD, 21205, USA

    Chi V. Dang

Authors
  1. Jung-whan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ping Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chi V. Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chi V. Dang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, Jw., Gao, P. & Dang, C.V. Effects of hypoxia on tumor metabolism. Cancer Metastasis Rev 26, 291–298 (2007). https://doi.org/10.1007/s10555-007-9060-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-007-9060-4

Keywords

Search

Navigation