Abstract
Oxygen is directly involved in many key pathophysiological processes. Oxygen deficiency, also known as hypoxia, could have adverse effects on mammalian cells, with ischemia in vital tissues being the most significant (Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol 164(6): 1875–1882, 2004); therefore, timely adaptive responses to variations in oxygen availability are essential for cellular homeostasis and survival. The most critical molecular event in hypoxic response is the activation and stabilization of a transcriptional factor termed hypoxia-induced factor-1 (HIF-1) that is responsible for the upregulation of many downstream effector genes, collectively known as hypoxia-responsive genes. Multiple key biological pathways such as proliferation, energy metabolism, invasion, and metastasis are governed by these genes; thus, HIF-1-mediated pathways are equally pivotal in both physiology and pathology.
As we gain knowledge on the molecular mechanisms underlying the regulation of HIF-1, a great focus has been placed on elucidating the cellular function of HIF-1, particularly the role of HIF-1 in cancer pathogenesis pathways such as proliferation, invasion, angiogenesis, and metastasis. In cancer, HIF-1 is directly involved in the shift of cancer tissues from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the Warburg effect. Although targeting HIF-1 as a cancer therapy seems like an extremely rational approach, owing to the complex network of its downstream effector genes, the development of specific HIF-1 inhibitors with fewer side effects and more specificity has not been achieved. Therefore, in this review, we provide a brief background about the function of HIF proteins in hypoxia response with a special emphasis on the unique role played by HIF-1α in cancer growth and invasiveness, in the hypoxia response context.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Michiels, C. (2004). Physiological and pathological responses to hypoxia. The American Journal of Pathology, 164(6), 1875–1882.
Warren, S. M., et al. (2001). Hypoxia regulates osteoblast gene expression. The Journal of Surgical Research, 99(1), 147–155.
Cramer, T., et al. (2003). HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell, 112(5), 645–657.
Hochachka, P. W., et al. (1996). Unifying theory of hypoxia tolerance: Molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proceedings of the National Academy of Sciences of the United States of America, 93(18), 9493–9498.
Denko, N., et al. (2003). Hypoxia actively represses transcription by inducing negative cofactor 2 (Dr1/DrAP1) and blocking preinitiation complex assembly. The Journal of Biological Chemistry, 278(8), 5744–5749.
Manalo, D. J., et al. (2005). Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood, 105(2), 659–669.
Semenza, G. L. (1998). Hypoxia-inducible factor 1: Master regulator of O2 homeostasis. Current Opinion in Genetics & Development, 8(5), 588–594.
Wenger, R. H. (2002). Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. The FASEB Journal, 16(10), 1151–1162.
Iyer, N. V., et al. (1998). Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes & Development, 12(2), 149–162.
Ryan, H. E., Lo, J., & Johnson, R. S. (1998). HIF-1 alpha is required for solid tumor formation and embryonic vascularization. The EMBO Journal, 17(11), 3005–3015.
Semenza, G. L. (2003). Targeting HIF-1 for cancer therapy. Nature Reviews. Cancer, 3(10), 721–732.
Schofield, C. J., & Ratcliffe, P. J. (2004). Oxygen sensing by HIF hydroxylases. Nature Reviews. Molecular Cell Biology, 5(5), 343–354.
Semenza, G. L., et al. (1991). Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proceedings of the National Academy of Sciences of the United States of America, 88(13), 5680–5684.
Semenza, G. L., & Wang, G. L. (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Molecular and Cellular Biology, 12(12), 5447–5454.
Wang, G. L., & Semenza, G. L. (1993). Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. The Journal of Biological Chemistry, 268(29), 21513–21518.
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(9), 4304–4308.
Richard, D. E., et al. (1999). p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. Journal of Biological Chemistry, 274(46), 32631–32637.
Carrero, P., et al. (2000). Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha. Molecular and Cellular Biology, 20(1), 402–415.
Duan, C. (2016). Hypoxia-inducible factor 3 biology: Complexities and emerging themes. American Journal of Physiology. Cell Physiology, 310(4), C260–C269.
Wang, G. L., et al. (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences of the United States of America, 92(12), 5510–5514.
Ema, M., et al. (1997). A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proceedings of the National Academy of Sciences of the United States of America, 94(9), 4273–4278.
Flamme, I., et al. (1997). HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Mechanisms of Development, 63(1), 51–60.
Hogenesch, J. B., et al. (1997). Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. The Journal of Biological Chemistry, 272(13), 8581–8593.
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(1), 72–82.
Huang, L. E., et al. (1996). Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. The Journal of Biological Chemistry, 271(50), 32253–32259.
Jiang, B. H., et al. (1997). Transactivation and inhibitory domains of hypoxia-inducible factor 1alpha. Modulation of transcriptional activity by oxygen tension. The Journal of Biological Chemistry, 272(31), 19253–19260.
Salceda, S., & Caro, J. (1997). Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. The Journal of Biological Chemistry, 272(36), 22642–22647.
Jiang, B. H., et al. (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(23), 5328–5335.
Chilov, D., et al. (1999). Induction and nuclear translocation of hypoxia-inducible factor-1 (HIF-1): Heterodimerization with ARNT is not necessary for nuclear accumulation of HIF-1alpha. Journal of Cell Science, 112(Pt 8), 1203–1212.
Wood, S. M., et al. (1996). The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression. Studies in ARNT-deficient cells. The Journal of Biological Chemistry, 271(25), 15117–15123.
Maltepe, E., et al. (1997). Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature, 386(6623), 403–407.
Swanson, H. I., & Bradfield, C. A. (1993). The AH-receptor: Genetics, structure and function. Pharmacogenetics, 3(5), 213–230.
Rowlands, J. C., & Gustafsson, J. A. (1997). Aryl hydrocarbon receptor-mediated signal transduction. Critical Reviews in Toxicology, 27(2), 109–134.
Bruick, R. K., & McKnight, S. L. (2001). A conserved family of prolyl-4-hydroxylases that modify HIF. Science, 294(5545), 1337–1340.
Jeong, J. W., et al. (2002). Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell, 111(5), 709–720.
Gradin, K., et al. (1996). Functional interference between hypoxia and dioxin signal transduction pathways: Competition for recruitment of the Arnt transcription factor. Molecular and Cellular Biology, 16(10), 5221–5231.
Huang, L. E., et al. (1998). Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proceedings of the National Academy of Sciences of the United States of America, 95(14), 7987–7992.
Pugh, C. W., et al. (1997). Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit. The Journal of Biological Chemistry, 272(17), 11205–11214.
O’Rourke, J. F., et al. (1999). Oxygen-regulated and transactivating domains in endothelial PAS protein 1: Comparison with hypoxia-inducible factor-1α. Journal of Biological Chemistry, 274(4), 2060–2071.
Srinivas, V., et al. (1999). Characterization of an oxygen/redox-dependent degradation domain of hypoxia-inducible factor alpha (HIF-alpha) proteins. Biochemical and Biophysical Research Communications, 260(2), 557–561.
Dayan, F., et al. (2008). A dialogue between the hypoxia-inducible factor and the tumor microenvironment. Cancer Microenvironment, 1(1), 53–68.
Wiesener, M. S., et al. (2003). Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. The FASEB Journal, 17(2), 271–273.
Onita, T., et al. (2002). Hypoxia-induced, perinecrotic expression of endothelial per-ARNT-Sim domain protein-1/hypoxia-inducible factor-2alpha correlates with tumor progression, vascularization, and focal macrophage infiltration in bladder cancer. Clinical Cancer Research, 8(2), 471–480.
Keith, B., Johnson, R. S., & Simon, M. C. (2011). HIF1alpha and HIF2alpha: Sibling rivalry in hypoxic tumour growth and progression. Nature Reviews. Cancer, 12(1), 9–22.
Leek, R. D., et al. (2002). Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in human breast cancer. Cancer Research, 62(5), 1326–1329.
Wiesener, M. S., et al. (1998). Induction of endothelial PAS domain protein-1 by hypoxia: Characterization and comparison with hypoxia-inducible factor-1alpha. Blood, 92(7), 2260–2268.
Stewart, M., et al. (2002). Expression of angiogenic factors and hypoxia inducible factors HIF 1, HIF 2 and CA IX in non-Hodgkin’s lymphoma. Histopathology, 40(3), 253–260.
Fukumura, D., et al. (1998). Tumor induction of VEGF promoter activity in stromal cells. Cell, 94(6), 715–725.
Flamme, I., Krieg, M., & Plate, K. H. (1998). Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of the transcription factor HRF/HIF-2alpha. The American Journal of Pathology, 153(1), 25–29.
Giatromanolaki, A., et al. (2001). Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. British Journal of Cancer, 85(6), 881–890.
Xia, G., et al. (2001). Regulation of vascular endothelial growth factor transcription by endothelial PAS domain protein 1 (EPAS1) and possible involvement of EPAS1 in the angiogenesis of renal cell carcinoma. Cancer, 91(8), 1429–1436.
Favier, J., et al. (2002). Angiogenesis and vascular architecture in pheochromocytomas: Distinctive traits in malignant tumors. The American Journal of Pathology, 161(4), 1235–1246.
Mazumdar, J., et al. (2010). HIF-2alpha deletion promotes Kras-driven lung tumor development. Proceedings of the National Academy of Sciences of the United States of America, 107(32), 14182–14187.
Kim, W. Y., et al. (2009). HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice. The Journal of Clinical Investigation, 119(8), 2160–2170.
Makino, Y., et al. (2002). Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus. The Journal of Biological Chemistry, 277(36), 32405–32408.
Hara, S., et al. (2001). Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: Suppression of HIF-mediated gene expression by HIF-3alpha. Biochemical and Biophysical Research Communications, 287(4), 808–813.
Maynard, M. A., et al. (2003). Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. The Journal of Biological Chemistry, 278(13), 11032–11040.
Maynard, M. A., et al. (2007). Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle, 6(22), 2810–2816.
Tanaka, T., et al. (2009). The human HIF (hypoxia-inducible factor)-3alpha gene is a HIF-1 target gene and may modulate hypoxic gene induction. The Biochemical Journal, 424(1), 143–151.
Heikkila, M., et al. (2011). Roles of the human hypoxia-inducible factor (HIF)-3alpha variants in the hypoxia response. Cellular and Molecular Life Sciences, 68(23), 3885–3901.
Michaud, J. L., et al. (2000). ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus. Mechanisms of Development, 90(2), 253–261.
Wang, G. L., & Semenza, G. L. (1995). Purification and characterization of hypoxia-inducible factor 1. The Journal of Biological Chemistry, 270(3), 1230–1237.
Keith, B., Adelman, D. M., & Simon, M. C. (2001). Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt. Proceedings of the National Academy of Sciences of the United States of America, 98(12), 6692–6697.
Drutel, G., et al. (1996). Cloning and selective expression in brain and kidney of ARNT2 homologous to the Ah receptor nuclear translocator (ARNT). Biochemical and Biophysical Research Communications, 225(2), 333–339.
Hirose, K., et al. (1996). cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor nuclear translocator (Arnt). Molecular and Cellular Biology, 16(4), 1706–1713.
Wang, G. L., & Semenza, G. L. (1996). Molecular basis of hypoxia-induced erythropoietin expression. Current Opinion in Hematology, 3(2), 156–162.
Camps, C., et al. (2014). Integrated analysis of microRNA and mRNA expression and association with HIF binding reveals the complexity of microRNA expression regulation under hypoxia. Molecular Cancer, 13, 28.
Kelly, B. D., et al. (2003). Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circulation Research, 93(11), 1074–1081.
Yun, Z., et al. (2002). Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: A mechanism for regulation of adipogenesis by hypoxia. Developmental Cell, 2(3), 331–341.
Balamurugan, K. (2016). HIF-1 at the crossroads of hypoxia, inflammation, and cancer. International Journal of Cancer, 138(5), 1058–1066.
Liu, W., et al. (2012). Targeted genes and interacting proteins of hypoxia inducible factor-1. International Journal of Biochemistry and Molecular Biology, 3(2), 165–178.
Pouyssegur, J., Dayan, F., & Mazure, N. M. (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature, 441(7092), 437–443.
Zelzer, E., et al. (1998). Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. The EMBO Journal, 17(17), 5085–5094.
Feldser, D., et al. (1999). Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Research, 59(16), 3915–3918.
Hellwig-Burgel, T., et al. (1999). Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. Blood, 94(5), 1561–1567.
Laughner, E., et al. (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(12), 3995–4004.
Fukuda, R., et al. (2002). Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. The Journal of Biological Chemistry, 277(41), 38205–38211.
Zhong, H., et al. (2000). Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: Implications for tumor angiogenesis and therapeutics. Cancer Research, 60(6), 1541–1545.
Sang, N., et al. (2003). MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. The Journal of Biological Chemistry, 278(16), 14013–14019.
Mylonis, I., et al. (2006). Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1alpha. The Journal of Biological Chemistry, 281(44), 33095–33106.
Page, E. L., et al. (2002). Induction of hypoxia-inducible factor-1alpha by transcriptional and translational mechanisms. The Journal of Biological Chemistry, 277(50), 48403–48409.
Kalousi, A., et al. (2010). Casein kinase 1 regulates human hypoxia-inducible factor HIF-1. Journal of Cell Science, 123(Pt 17), 2976–2986.
To, K. K., et al. (2006). The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repression. The EMBO Journal, 25(20), 4784–4794.
Maxwell, P. H., et al. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399(6733), 271–275.
Mailloux, R. J., Puiseux-Dao, S., & Appanna, V. D. (2009). Alpha-ketoglutarate abrogates the nuclear localization of HIF-1alpha in aluminum-exposed hepatocytes. Biochimie, 91(3), 408–415.
Lando, D., et al. (2002). FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes & Development, 16(12), 1466–1471.
Berra, E., et al. (2003). HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. The EMBO Journal, 22(16), 4082–4090.
Jaakkola, P., et al. (2001). Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292(5516), 468–472.
Schofield, C. J., & Ratcliffe, P. J. (2005). Signalling hypoxia by HIF hydroxylases. Biochemical and Biophysical Research Communications, 338(1), 617–626.
Koivunen, P., et al. (2007). An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha. The Journal of Biological Chemistry, 282(42), 30544–30552.
Hewitson, K. S., et al. (2002). Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. The Journal of Biological Chemistry, 277(29), 26351–26355.
Lee, C., et al. (2003). Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and von Hippel-Lindau. The Journal of Biological Chemistry, 278(9), 7558–7563.
Soni, S., & Padwad, Y. S. (2017). HIF-1 in cancer therapy: Two decade long story of a transcription factor. Acta Oncologica, 56(4), 503–515.
Lim, J. H., et al. (2010). Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Molecular Cell, 38(6), 864–878.
Chandel, N. S., et al. (1998). Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proceedings of the National Academy of Sciences of the United States of America, 95(20), 11715–11720.
Chandel, N. S., et al. (2000). Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: A mechanism of O2 sensing. The Journal of Biological Chemistry, 275(33), 25130–25138.
Schroedl, C., et al. (2002). Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species. American Journal of Physiology. Lung Cellular and Molecular Physiology, 283(5), L922–L931.
Gerald, D., et al. (2004). JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell, 118(6), 781–794.
Kimura, H., et al. (2000). Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: Control of hypoxia-inducible factor-1 activity by nitric oxide. Blood, 95(1), 189–197.
Palmer, L. A., Gaston, B., & Johns, R. A. (2000). Normoxic stabilization of hypoxia-inducible factor-1 expression and activity: Redox-dependent effect of nitrogen oxides. Molecular Pharmacology, 58(6), 1197–1203.
Sandau, K. B., Faus, H. G., & Brune, B. (2000). Induction of hypoxia-inducible-factor 1 by nitric oxide is mediated via the PI 3K pathway. Biochemical and Biophysical Research Communications, 278(1), 263–267.
Sandau, K. B., Fandrey, J., & Brune, B. (2001). Accumulation of HIF-1alpha under the influence of nitric oxide. Blood, 97(4), 1009–1015.
Liu, Y., et al. (1998). Carbon monoxide and nitric oxide suppress the hypoxic induction of vascular endothelial growth factor gene via the 5′ enhancer. The Journal of Biological Chemistry, 273(24), 15257–15262.
Sogawa, K., et al. (1998). Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 95(13), 7368–7373.
Yin, J. H., et al. (2000). iNOS expression inhibits hypoxia-inducible factor-1 activity. Biochemical and Biophysical Research Communications, 279(1), 30–34.
Wenger, R. H., Stiehl, D. P., & Camenisch, G. (2005). Integration of oxygen signaling at the consensus HRE. Science’s STKE, 2005(306), re12.
Semenza, G. L., et al. (1994). Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. The Journal of Biological Chemistry, 269(38), 23757–23763.
Jiang, B. H., et al. (1996). Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. The Journal of Biological Chemistry, 271(30), 17771–17778.
Wenger, R. H. (2000). Mammalian oxygen sensing, signalling and gene regulation. The Journal of Experimental Biology, 203(Pt 8), 1253–1263.
Minchenko, A., et al. (2002). 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. The Journal of Biological Chemistry, 277(8), 6183–6187.
Hayashi, M., et al. (2004). Induction of glucose transporter 1 expression through hypoxia-inducible factor 1alpha under hypoxic conditions in trophoblast-derived cells. The Journal of Endocrinology, 183(1), 145–154.
Liu, Y., et al. (2009). The expression and significance of HIF-1alpha and GLUT-3 in glioma. Brain Research, 1304, 149–154.
Zhang, H., et al. (2008). Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. The Journal of Biological Chemistry, 283(16), 10892–10903.
Sowter, H. M., et al. (2001). HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Research, 61(18), 6669–6673.
Lu, C. W., et al. (2008). Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. The Journal of Biological Chemistry, 283(42), 28106–28114.
Bellot, G., et al. (2009). Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Molecular and Cellular Biology, 29(10), 2570–2581.
Ivan, M., et al. (2008). Hypoxia response and microRNAs: No longer two separate worlds. Journal of Cellular and Molecular Medicine, 12(5A), 1426–1431.
Devlin, C., et al. (2011). miR-210: More than a silent player in hypoxia. IUBMB Life, 63(2), 94–100.
Chan, S. Y., et al. (2009). MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metabolism, 10(4), 273–284.
Favaro, E., et al. (2010). MicroRNA-210 regulates mitochondrial free radical response to hypoxia and Krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PLoS One, 5(4), e10345.
Metallo, C. M., et al. (2011). Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature, 481(7381), 380–384.
Wise, D. R., et al. (2011). Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proceedings of the National Academy of Sciences of the United States of America, 108(49), 19611–19616.
Du, W., et al. (2017). HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nature Communications, 8(1), 1769.
Griffiths, J. R., et al. (2002). Metabolic changes detected by in vivo magnetic resonance studies of HEPA-1 wild-type tumors and tumors deficient in hypoxia-inducible factor-1beta (HIF-1beta): Evidence of an anabolic role for the HIF-1 pathway. Cancer Research, 62(3), 688–695.
Younes, M., Lechago, L. V., & Lechago, J. (1996). Overexpression of the human erythrocyte glucose transporter occurs as a late event in human colorectal carcinogenesis and is associated with an increased incidence of lymph node metastases. Clinical Cancer Research, 2(7), 1151–1154.
Semenza, G. L. (2009). Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Seminars in Cancer Biology, 19(1), 12–16.
Pinheiro, C., et al. (2012). Role of monocarboxylate transporters in human cancers: State of the art. Journal of Bioenergetics and Biomembranes, 44(1), 127–139.
Chiche, J., Brahimi-Horn, M. C., & Pouyssegur, J. (2010). Tumour hypoxia induces a metabolic shift causing acidosis: A common feature in cancer. Journal of Cellular and Molecular Medicine, 14(4), 771–794.
Swietach, P., et al. (2008). Tumor-associated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growths. The Journal of Biological Chemistry, 283(29), 20473–20483.
Gatenby, R. A., et al. (2007). Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. British Journal of Cancer, 97(5), 646–653.
Christofk, H. R., et al. (2008). The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature, 452(7184), 230–233.
Luo, W., et al. (2011). Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell, 145(5), 732–744.
Gao, X., et al. (2012). Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Molecular Cell, 45(5), 598–609.
Dvorak, H. F. (1986). Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. The New England Journal of Medicine, 315(26), 1650–1659.
Vaupel, P., Schaefer, C., & Okunieff, P. (1994). Intracellular acidosis in murine fibrosarcomas coincides with ATP depletion, hypoxia, and high levels of lactate and total pi. NMR in Biomedicine, 7(3), 128–136.
Denko, N. C., & Giaccia, A. J. (2001). Tumor hypoxia, the physiological link between Trousseau’s syndrome (carcinoma-induced coagulopathy) and metastasis. Cancer Research, 61(3), 795–798.
Vaupel, P., & Mayer, A. (2014). Hypoxia in tumors: Pathogenesis-related classification, characterization of hypoxia subtypes, and associated biological and clinical implications. Advances in Experimental Medicine and Biology, 812, 19–24.
Zhong, H., et al. (1999). Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Research, 59(22), 5830–5835.
Talks, K. L., et al. (2000). The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. The American Journal of Pathology, 157(2), 411–421.
Koshikawa, N., et al. (2003). Constitutive upregulation of hypoxia-inducible factor-1alpha mRNA occurring in highly metastatic lung carcinoma cells leads to vascular endothelial growth factor overexpression upon hypoxic exposure. Oncogene, 22(43), 6717–6724.
Hockel, M., et al. (1996). Hypoxia and radiation response in human tumors. Seminars in Radiation Oncology, 6(1), 3–9.
Hockel, M., et al. (1998). Tumor hypoxia in pelvic recurrences of cervical cancer. International Journal of Cancer, 79(4), 365–369.
Hockel, M., et al. (1999). Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Research, 59(18), 4525–4528.
Semenza, G. L. (2011). Oxygen sensing, homeostasis, and disease. The New England Journal of Medicine, 365(6), 537–547.
Doedens, A. L., et al. (2010). Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Research, 70(19), 7465–7475.
Takeda, N., et al. (2010). Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes & Development, 24(5), 491–501.
Noman, M. Z., et al. (2014). PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. The Journal of Experimental Medicine, 211(5), 781–790.
Lee, J. H., et al. (2015). E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1α to maintain regulatory T cell stability and suppressive capacity. Immunity, 42(6), 1062–1074.
Okegawa, T., et al. (2004). The role of cell adhesion molecule in cancer progression and its application in cancer therapy. Acta Biochimica Polonica, 51(2), 445–457.
Cowden Dahl, K. D., et al. (2005). Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression. Molecular Biology of the Cell, 16(4), 1901–1912.
Ryu, M. H., et al. (2010). Hypoxia-inducible factor-1alpha mediates oral squamous cell carcinoma invasion via upregulation of alpha5 integrin and fibronectin. Biochemical and Biophysical Research Communications, 393(1), 11–15.
Lee, S. H., Lee, Y. J., & Han, H. J. (2011). Role of hypoxia-induced fibronectin-integrin beta1 expression in embryonic stem cell proliferation and migration: Involvement of PI3K/Akt and FAK. Journal of Cellular Physiology, 226(2), 484–493.
Krishnamachary, B., et al. (2006). Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Research, 66(5), 2725–2731.
Zhang, Y., Fan, N., & Yang, J. (2015). Expression and clinical significance of hypoxia-inducible factor 1alpha, snail and E-cadherin in human ovarian cancer cell lines. Molecular Medicine Reports, 12(3), 3393–3399.
Barak, V., et al. (2011). VEGF as a biomarker for metastatic Uveal melanoma in humans. Current Eye Research, 36(4), 386–390.
Semenza, G. L. (2012). Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy. Trends in Pharmacological Sciences, 33(4), 207–214.
Hasan, N. M., et al. (1998). Hypoxia facilitates tumour cell detachment by reducing expression of surface adhesion molecules and adhesion to extracellular matrices without loss of cell viability. British Journal of Cancer, 77(11), 1799–1805.
Peng, J. K., et al. (2018). Etaypoxia-inducible factor 1-alpha promotes colon cell proliferation and migration by upregulating AMPK-related protein kinase 5 under hypoxic conditions. Oncology Letters, 15(3), 3639–3645.
Suzuki, A., et al. (2003). ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or UV irradiation. Oncogene, 22(40), 6177–6182.
Suzuki, A., et al. (2004). Regulation of caspase-6 and FLIP by the AMPK family member ARK5. Oncogene, 23(42), 7067–7075.
Lu, S., et al. (2013). ARK5 promotes glioma cell invasion, and its elevated expression is correlated with poor clinical outcome. European Journal of Cancer, 49(3), 752–763.
Lester, R. D., et al. (2005). Erythropoietin promotes MCF-7 breast cancer cell migration by an ERK/mitogen-activated protein kinase-dependent pathway and is primarily responsible for the increase in migration observed in hypoxia. The Journal of Biological Chemistry, 280(47), 39273–39277.
Cannito, S., et al. (2008). Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells. Carcinogenesis, 29(12), 2267–2278.
Matsuoka, J., et al. (2013). Hypoxia stimulates the EMT of gastric cancer cells through autocrine TGFbeta signaling. PLoS One, 8(5), e62310.
Yang, M. H., et al. (2008). Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nature Cell Biology, 10(3), 295–305.
Lendahl, U., et al. (2009). Generating specificity and diversity in the transcriptional response to hypoxia. Nature Reviews Genetics, 10(12), 821–832.
Tsai, Y. P., & Wu, K. J. (2012). Hypoxia-regulated target genes implicated in tumor metastasis. Journal of Biomedical Science, 19, 102.
Chu, C. Y., et al. (2016). CA IX is upregulated in CoCl2-induced hypoxia and associated with cell invasive potential and a poor prognosis of breast cancer. International Journal of Oncology, 48(1), 271–280.
Evans, A. J., et al. (2007). VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Molecular and Cellular Biology, 27(1), 157–169.
de Herreros, A. G., et al. (2010). Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. Journal of Mammary Gland Biology and Neoplasia, 15(2), 135–147.
Luo, Y., et al. (2006). Over-expression of hypoxia-inducible factor-1alpha increases the invasive potency of LNCaP cells in vitro. BJU International, 98(6), 1315–1319.
O’Toole, E. A., et al. (2008). Hypoxia induces epidermal keratinocyte matrix metalloproteinase-9 secretion via the protein kinase C pathway. Journal of Cellular Physiology, 214(1), 47–55.
Lin, M. T., et al. (2008). Involvement of hypoxia-inducing factor-1alpha-dependent plasminogen activator inhibitor-1 up-regulation in Cyr61/CCN1-induced gastric cancer cell invasion. The Journal of Biological Chemistry, 283(23), 15807–15815.
Buchler, P., et al. (2009). Transcriptional regulation of urokinase-type plasminogen activator receptor by hypoxia-inducible factor 1 is crucial for invasion of pancreatic and liver cancer. Neoplasia, 11(2), 196–206.
Pennacchietti, S., et al. (2003). Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell, 3(4), 347–361.
Ishikawa, T., et al. (2009). Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma. Oncology Reports, 21(3), 707–712.
Li, Y., et al. (2009). Hypoxia induced CCR7 expression via HIF-1alpha and HIF-2alpha correlates with migration and invasion in lung cancer cells. Cancer Biology & Therapy, 8(4), 322–330.
Erler, J. T., et al. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature, 440(7088), 1222–1226.
Funasaka, T., et al. (2005). Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. The FASEB Journal, 19(11), 1422–1430.
Staller, P., et al. (2003). Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature, 425(6955), 307–311.
Pan, J., et al. (2006). Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. Molecular Cancer, 5, 56.
Castillo Bennett, J., et al. (2018). Hypoxia-induced Caveolin-1 expression promotes migration and invasion of tumor cells. Current Molecular Medicine, 18(4), 199–206.
Krishnamachary, B., et al. (2003). Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Research, 63(5), 1138–1143.
Nikitenko, L. L., et al. (2003). Transcriptional regulation of the CRLR gene in human microvascular endothelial cells by hypoxia. The FASEB Journal, 17(11), 1499–1501.
Pugh, C. W., & Ratcliffe, P. J. (2003). Regulation of angiogenesis by hypoxia: Role of the HIF system. Nature Medicine, 9(6), 677–684.
Kotch, L. E., et al. (1999). Defective vascularization of HIF-1alpha-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Developmental Biology, 209(2), 254–267.
Maruggi, M., et al. (2019). Absence of HIF1A leads to glycogen accumulation and an inflammatory response that enables pancreatic tumor growth. Cancer Research, 79(22), 5839–5848.
Cheng, J., et al. (2007). SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell, 131(3), 584–595.
Xu, Y., et al. (2010). Induction of SENP1 in endothelial cells contributes to hypoxia-driven VEGF expression and angiogenesis. The Journal of Biological Chemistry, 285(47), 36682–36688.
Riva, C., et al. (1998). Cellular physiology and molecular events in hypoxia-induced apoptosis. Anticancer Research, 18(6b), 4729–4736.
Hammond, E. M., Dorie, M. J., & Giaccia, A. J. (2003). ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. The Journal of Biological Chemistry, 278(14), 12207–12213.
Akakura, N., et al. (2001). Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Research, 61(17), 6548–6554.
Carmeliet, P., et al. (1998). Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature, 394(6692), 485–490.
Santore, M. T., et al. (2002). Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells. American Journal of Physiology. Lung Cellular and Molecular Physiology, 282(4), L727–L734.
Kumar, H., & Choi, D. K. (2015). Hypoxia inducible factor pathway and physiological adaptation: A cell survival pathway? Mediators of Inflammation, 2015, 584758.
McClintock, D. S., et al. (2002). Bcl-2 family members and functional electron transport chain regulate oxygen deprivation-induced cell death. Molecular and Cellular Biology, 22(1), 94–104.
Yoo, B. H., et al. (2009). Hypoxia-induced downregulation of autophagy mediator Beclin 1 reduces the susceptibility of malignant intestinal epithelial cells to hypoxia-dependent apoptosis. Autophagy, 5(8), 1166–1179.
Soengas, M. S., et al. (1999). Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science, 284(5411), 156–159.
Li, F., et al. (2015). Curcumin induces p53-independent necrosis in H1299 cells via a mitochondria-associated pathway. Molecular Medicine Reports, 12(5), 7806–7814.
Shimizu, S., et al. (1995). Prevention of hypoxia-induced cell death by Bcl-2 and Bcl-xL. Nature, 374(6525), 811–813.
Kim, J. Y., et al. (2004). BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. The Journal of Experimental Medicine, 199(1), 113–124.
Zagzag, D., et al. (2000). Expression of hypoxia-inducible factor 1alpha in brain tumors: Association with angiogenesis, invasion, and progression. Cancer, 88(11), 2606–2618.
Schindl, M., et al. (2002). Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clinical Cancer Research, 8(6), 1831–1837.
Bos, R., et al. (2003). Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer, 97(6), 1573–1581.
Aebersold, D. M., et al. (2001). Expression of hypoxia-inducible factor-1alpha: A novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Research, 61(7), 2911–2916.
Beasley, N. J., et al. (2002). Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: Relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Research, 62(9), 2493–2497.
Koukourakis, M. I., et al. (2002). Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. International Journal of Radiation Oncology, Biology, Physics, 53(5), 1192–1202.
Birner, P., et al. (2001). Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: Its impact on prognosis and on response to chemotherapy. Clinical Cancer Research, 7(6), 1661–1668.
Zhang, X., et al. (2019). Interaction between p53 and Ras signaling controls cisplatin resistance via HDAC4- and HIF-1alpha-mediated regulation of apoptosis and autophagy. Theranostics, 9(4), 1096–1114.
Jiang, X., et al. (2019). The correlation between NEDD4L and HIF-1alpha levels as a gastric cancer prognostic marker. International Journal of Medical Sciences, 16(11), 1517–1524.
Koukourakis, M. I., et al. (2001). Hypoxia inducible factor (HIF-1a and HIF-2a) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy. Cancer Research, 61(5), 1830–1832.
Wigerup, C., Pahlman, S., & Bexell, D. (2016). Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacology & Therapeutics, 164, 152–169.
Masoud, G. N., & Li, W. (2015). HIF-1alpha pathway: Role, regulation and intervention for cancer therapy. Acta Pharmaceutica Sinica B, 5(5), 378–389.
Hu, Y., Liu, J., & Huang, H. (2013). Recent agents targeting HIF-1alpha for cancer therapy. Journal of Cellular Biochemistry, 114(3), 498–509.
Falchook, G. S., et al. (2014). Targeting hypoxia-inducible factor-1alpha (HIF-1alpha) in combination with antiangiogenic therapy: A phase I trial of bortezomib plus bevacizumab. Oncotarget, 5(21), 10280–10292.
Ban, H. S., et al. (2016). Hypoxia-inducible factor (HIF) inhibitors: A patent survey (2011–2015). Expert Opinion on Therapeutic Patents, 26(3), 309–322.
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Elzakra, N., Kim, Y. (2021). HIF-1α Metabolic Pathways in Human Cancer. In: Hu, S. (eds) Cancer Metabolomics. Advances in Experimental Medicine and Biology, vol 1280. Springer, Cham. https://doi.org/10.1007/978-3-030-51652-9_17
Download citation
DOI: https://doi.org/10.1007/978-3-030-51652-9_17
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-51651-2
Online ISBN: 978-3-030-51652-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)