HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations
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Hypoxia occurs frequently in human cancers and induces adaptive changes in cell metabolism that include a switch from oxidative phosphorylation to glycolysis, increased glycogen synthesis, and a switch from glucose to glutamine as the major substrate for fatty acid synthesis. This broad metabolic reprogramming is coordinated at the transcriptional level by HIF-1, which functions as a master regulator to balance oxygen supply and demand. HIF-1 is also activated in cancer cells by tumor suppressor (e.g., VHL) loss of function and oncogene gain of function (leading to PI3K/AKT/mTOR activity) and mediates metabolic alterations that drive cancer progression and resistance to therapy. Inhibitors of HIF-1 or metabolic enzymes may impair the metabolic flexibility of cancer cells and make them more sensitive to anticancer drugs.
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HIFs regulate a switch from glucose to glutamine metabolism to produce acetyl-CoA in fatty acid synthesis.
“HIFs regulate a switch from glucose to glutamine metabolism to produce acetyl-CoA in fatty acid synthesis (Semenza, 2013).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Semenza, 2013
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Zhang, H., Wong, C. C. L., Wei, H., Gilkes, D. M., Korangath, P., Chaturvedi, P., Schito, L., Chen, J., Krishnamachary, B., Winnard, P. T., et al. (2012) · Oncogene · doi:10.1038/onc.2011.365 · Cited by 326 · see citing works
Self-citationRetractedActivation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
Forsythe, J. A., Jiang, B.-H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., & Semenza, G. L. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4604 · Cited by 3,981 · see citing works
Self-citationOxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251 · see citing works
Cellular and developmental control of O <sub>2</sub> homeostasis by hypoxia-inducible factor 1α
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., et al. (1998) · Genes & Development · doi:10.1101/gad.12.2.149 · Cited by 2,476 · see citing works
Self-citationSignal transduction by reactive oxygen species
Finkel, T. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201102095 · Cited by 2,322 · see citing works
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108 · cited 1× · see citing works
“…in VHL directly block the ubiquitination of HIF-α subunits, mutations in the genes encoding succinate dehydrogenase (SDH) and fumarate hydratase (FH) block ubiquitination indirectly by increasing the concentration of TCA cycle intermediates that inhibit prolyl hydroxylase activity (91–93).”
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791 · see citing works
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
Semenza, G. L. (2010) · Oncogene · doi:10.1038/onc.2009.441 · Cited by 1,712 · see citing works
Self-citationHIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693 · see citing works
Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C., & Semenza, G. L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.12.3995-4004.2001 · Cited by 1,256 · cited 1× · see citing works
“…α synthesis as a result of PI3K and AKT signaling that stimulates mTOR activity, which stimulates translation of HIF1A mRNA into protein by phosphorylation of eIF4E binding protein (78, 80). mTOR has also been reported to stimulate HIF-1 α stabilization and transactivation domain function (81).”
Self-citationTranscriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1
Manalo, D. J., Rowan, A., Lavoie, T., Natarajan, L., Kelly, B. D., Ye, S. Q., Garcia, J. G. N., & Semenza, G. L. (2005) · Blood · doi:10.1182/blood-2004-07-2958 · Cited by 1,154 · see citing works
Self-citationGlioma-Derived Mutations in <i>IDH1</i> Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., et al. (2009) · Science · doi:10.1126/science.1170944 · Cited by 1,119 · see citing works
Wise, D. R., Ward, P. S., Shay, J. E. S., Cross, J. R., Gruber, J. J., Sachdeva, U. M., Platt, J. M., DeMatteo, R. G., Simon, M. C., & Thompson, C. B. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117773108 · Cited by 975 · see citing works
Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α
Ravi, R., Mookerjee, B., Bhujwalla, Z. M., Sutter, C. H., Artemov, D., Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., & Bedi, A. (2000) · Genes & Development · doi:10.1101/gad.14.1.34 · Cited by 967 · see citing works
Self-citationIsaacs, J. S., Jung, Y. J., Mole, D. R., Lee, S., Torres-Cabala, C., Chung, Y.-L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.017 · Cited by 958 · see citing works
High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq
Schödel, J., Oikonomopoulos, S., Ragoussis, J., Pugh, C. W., Ratcliffe, P. J., & Mole, D. R. (2011) · Blood · doi:10.1182/blood-2010-10-314427 · Cited by 724 · see citing works
Losman, J.-A., Looper, R. E., Koivunen, P., Lee, S., Schneider, R. K., McMahon, C., Cowley, G. S., Root, D. E., Ebert, B. L., & Kaelin, W. G. (2013) · Science · doi:10.1126/science.1231677 · Cited by 703 · see citing works
Chan, S. Y., Zhang, Y.-Y., Hemann, C., Mahoney, C. E., Zweier, J. L., & Loscalzo, J. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.08.015 · Cited by 702 · see citing works
The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type
Yuneva, M. O., Fan, T. W. M., Allen, T. D., Higashi, R. M., Ferraris, D. V., Tsukamoto, T., Matés, J. M., Alonso, F. J., Wang, C., Seo, Y., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2011.12.015 · Cited by 639 · see citing works
HIF-Dependent Antitumorigenic Effect of Antioxidants In Vivo
Gao, P., Zhang, H., Dinavahi, R., Li, F., Xiang, Y., Raman, V., Bhujwalla, Z. M., Felsher, D. W., Cheng, L., Pevsner, J., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.004 · Cited by 523 · see citing works
Self-citationRegulation of cancer cell metabolism by hypoxia-inducible factor 1
Semenza, G. L. (2009) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2008.11.009 · Cited by 469 · see citing works
Self-citationRole of monocarboxylate transporters in human cancers: state of the art
Pinheiro, C., Longatto-Filho, A., Azevedo-Silva, J., Casal, M., Schmitt, F. C., & Baltazar, F. (2012) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-012-9428-1 · Cited by 368 · see citing works
Favaro, E., Ramachandran, A., McCormick, R., Gee, H., Blancher, C., Crosby, M., Devlin, C., Blick, C., Buffa, F., Li, J.-L., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010345 · Cited by 324 · cited 1× · see citing works
“Among the targets of miR-210 that are downregulated in hypoxic cells are mRNAs encoded by the ISCU gene, which encodes an iron-sulfur cluster assembly enzyme that is required for the activity of mitochondrial electron transport complex I (41, 42).”
Schito, L., Rey, S., Tafani, M., Zhang, H., Wong, C. C.-L., Russo, A., Russo, M. A., & Semenza, G. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1214019109 · Cited by 224 · see citing works
Self-citationRapisarda, A., Hollingshead, M., Uranchimeg, B., Bonomi, C. A., Borgel, S. D., Carter, J. P., Gehrs, B., Raffeld, M., Kinders, R. J., Parchment, R., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0274 · Cited by 171 · see citing works
Lau, K. W., Tian, Y.-M., Raval, R. R., Ratcliffe, P. J., & Pugh, C. W. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6603675 · Cited by 104 · see citing works
Flagged first, then by citations
Research works printed but not linked: 74
- Wang GL, Semenza GL. Purification and character- ization of hypoxia-inducible factor 1. J Biol Chem. 1995;270(3):1230-1237.
- Wang GL, Jiang BH, Rue EA, Semenza GL. Hypox- ia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510-5514.
- Semenza GL, et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydroge- nase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 1996;271(51):32529-32537.
- Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription fac- tor selectively expressed in endothelial cells. Genes Dev. 1997;11(1):72-82.
- Wiesener MS, et al. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1α. Blood. 1998;92(7):2260-2268.
- Hampton-Smith RJ, Peet DJ. From polyps to peo- ple: a highly familiar response to hypoxia. Ann N Y Acad Sci. 2009;1177:19-29.
- Loenarz C, et al. The hypoxia-inducible transcrip- tion factor pathway regulates oxygen sensing in the simplest animal, Trichoplax adhaerens. EMBO Rep. 2011;12(1):63-70.
- Zhong H, et al. Overexpression of hypoxia-induc- ible factor 1α in common human cancers and their metastases. Cancer Res. 1999;59(22):5830-5835.
- Talks KL, et al. The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associ- ated macrophages. Am J Pathol. 2000;157(2):411-421.
- Mole DR, et al. Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF- 2α DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem. 2009; 284(25):16767-16775.
- Xia X, et al. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci U S A. 2009;106(11):4260-4265.
- Vaupel P, Mayer A, Höckel M. Tumor hypoxia and malignant progression. Meth Enzymol. 2004;381:335-354.
- Kroeger N, et al. Deletions of chromosomes 3p and 14q molecularly subclassify clear cell renal cell car- cinoma. Cancer. 2013;119(8):1547-1554.
- Imamura T, et al. HIF-1α and HIF-2α have divergent roles in colon cancer. Int J Cancer. 2009;124(4):763-771.
- Keith B, Johnson RS, Simon MC. HIF-1α and HIF- 2α: sibling rivalry in hypoxic tumor growth and progression. Nat Rev Cancer. 2011;12(1):9-22.
- Mole DR, et al. Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF- 2α DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem. 2009;284(25):16767-16775.
- Rey S, Semenza GL. Hypoxia-inducible factor-1-de- pendent mechanisms of vascularization and vascu- lar remodelling. Cardiovasc Res. 2010;86(2):236-242.
- Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10(6):417-427.
- Semenza GL. Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. Trends Mol Med. 2012;18(9):534-543.
- Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE. HIF-1α induces cell cycle arrest by functionally counteracting Myc. EMBO J. 2004;23(9):1949-1956.
- Kaidi A, Williams AC, Paraskeva C. Interaction between β-catenin and HIF-1 promotes cellular adap- tation to hypoxia. Nat Cell Biol. 2007;9(2):210-217.
- Corn PG, et al. Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biol Ther. 2005;4(11):1285-1294.
- Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehy- drogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3(3):177-185.
- Zhang H, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008;283(16):10892-10903.
- Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3(3):187-197.
- Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 2001;61(18):6669-6673.
- Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-induc- ible factor-1 promotes metabolic switch and drug resistance. J Biol Chem. 2008;283(42):28106-28114.
- Bellot G, et al. Hypoxia-induced autophagy is medi- ated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009;29(10):2570-2581.
- Chandel NS, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-in- ducible factor-1α during hypoxia: a mechanism of O2 sensing. J Biol Chem. 2000;275(33):25130-25138.
- Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007;129(1):111-122.
- Lum JJ, et al. The transcription factor HIF-1α plays a critical role in the growth factor-dependent reg- ulation of both aerobic and anaerobic glycolysis. Genes Dev. 2007;21(9):1037-1049.
- Devlin C, Greco S, Martelli F, Ivan M. miR-210: More than a silent player in hypoxia. IUBMB Life. 2011;63(2):94-100.
- Cuezva JM, et al. The bioenergetic signature of cancer: a marker of tumor progression. Cancer Res. 2002;62(22):6674-6681.
- Suda T, Takubo K, Semenza GL. Metabolic regu- lation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011;9(4):298-310.
- Lagadinou ED, et al. BCL-2 inhibition targets oxi- dative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12(3):329-341.
- Chiche J, Brahimi-Horn MC, Pouysségur J. Tumor hypoxia induces a metabolic shift causing acido- sis: a common feature in cancer. J Cell Mol Med. 2010;14(4):771-794.
- Swietach P, Wigfield S, Cobden P, Supuran CT, Harris AL, Vaughan-Jones RD. Tumor-associ- ated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growths. J Biol Chem. 2008;283(29):20473-20483.
- Gatenby RA, et al. Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br J Cancer. 2007;97(5):646-653.
- Sonveaux P, et al. Targeting lactate-fueled respira- tion selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118(12):3930-3942.
- Pescador N, et al. Hypoxia promotes glycogen accu- mulation through hypoxia inducible factor (HIF)- mediated induction of glycogen synthase 1. PLoS One. 2010;5(3):e9644.
- Favaro E, et al. Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab. 2012;16(6):751-764.
- Mimura I, et al. Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by coopera- tive interaction of hypoxia-inducible factor 1 and KDM3A. Mol Cell Biol. 2012;32(15):3018-3032.
- Kondoh H, et al. Glycolytic enzymes can modulate cellular life span. Cancer Res. 2005;65(1):177-185.
- Hitosugi T, et al. Phosphoglycerate mutase 1 coor- dinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell. 2012;22(5):585-600.
- Clower CV, et al. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci U S A. 2010;107(5):1894-1899.
- David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 2010;463(7279):364-368.
- Chen M, David CJ, Manley JL. Concentration-de- pendent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins. Nat Struct Mol Biol. 2012;19(3):346-354.
- Wang Z, et al. Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons. J Mol Cell Biol. 2012;4(2):79-87.
- Christofk HR, et al. The M2 splice isoform of pyru- vate kinase is important for cancer metabolism and tumor growth. Nature. 2008;452(7184):230-233.
- Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC. Pyruvate kinase M2 is a phos- photyrosine-binding protein. Nature. 2008; 452(7184):181-186.
- Chaneton B, et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature. 2012;491(7424):458-462.
- Keller KE, Tan IS, Lee YS. SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions. Science. 2012;338(6110):1069-1072.
- Lv L, et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chap- erone-mediated autophagy and promotes tumor growth. Mol Cell. 2011;42(6):719-730.
- Anastasiou D, et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science. 2011; 334(6060):1278-1283.
- Lee J, Kim HK, Han YM, Kim J. Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription. Int J Biochem Cell Biol. 2008;40(5):1043-1054.
- Luo W, et al. Pyruvate kinase M2 is a PHD3-stim- ulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145(5):732-744.
- Yang W, et al. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature. 2011;480(7375):118-122.
- Gao X, Wang H, Yang JJ, Liu X, Liu ZR. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell. 2012;45(5):598-609.
- Zhong H, et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth fac- tor/phosphatidylinositol 3-kinase/PTEN/AKT/ FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and thera- peutics. Cancer Res. 2000;60(6):1541-1545.
- Zundel W, et al. Loss of PTEN facilitates HIF-1-medi- ated gene expression. Genes Dev. 2000;14(4):391-396.
- Hudson CC, et al. Regulation of hypoxia-induc- ible factor 1α expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002;22(20):7004-7014.
- Steck TL, Kaufman S, Bader JP. Glycolysis in chick embryo cell cultures transformed by Rous sarcoma virus. Cancer Res. 1968;28(8):1611-1619.
- Singh VN, Singh M, August JT, Horecker BL. Alterations in glucose metabolism in chick-em- bryo cells transformed by Rous sarcoma virus: intracellular levels of glycolytic intermediates. Proc Natl Acad Sci U S A. 1974;71(10):4129-4132.
- Carroll RC, Ash JF, Vogt PK, Singer SJ. Reversion of transformed glycolysis to normal by inhi- bition of protein synthesis in rat kidney cells infected with temperature-sensitive mutant of Rous sarcoma virus. Proc Natl Acad Sci U S A. 1978; 75(10):5015-5019.
- Jiang BH, Agani F, Passaniti A, Semenza GL. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 1997;57(23):5328-5335.
- Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer. 2008;8(11):865-873.
- Maxwell PH, et al. The tumor suppressor pro- tein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271-275.
- Mandriota SJ, et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell. 2002;1(5):459-468.
- Zhang H, et al. HIF-1 inhibits mitochondrial bio- genesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activ- ity. Cancer Cell. 2007;11(5):407-420.
- Warburg O. Über den stoffwechsel der carcinom- zelle. Klin Wochenschr. 1925;4:534-536.
- Pollard PJ, et al. Accumulation of Krebs cycle inter- mediates and over-expression of HIF-1a in tumors which result from germline FH and SDH muta- tions. Hum Mol Genet. 2005;14(15):2231-2239.
- Koivunen P, et al. Transformation by the (R)-enan- tiomer of 2-hydroxyglutarate linked to EGLN acti- vation. Nature. 2012;483(7390):484-488.
- Sherbenou DW, Druker BJ. Applying the discov- ery of the Philadelphia chromosome. J Clin Invest. 2007;117(8):2067-2074.
- Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sill- aber C. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1α, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood. 2002;100(10):3767-3775.
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Intlekofer, A. M., Dematteo, R. G., Venneti, S., Finley, L. W. S., Lu, C., Judkins, A. R., Rustenburg, A. S., Grinaway, P. B., Chodera, J. D., Cross, J. R., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.023 · Cited by 513 · see citing works
Samanta, D., Gilkes, D. M., Chaturvedi, P., Xiang, L., & Semenza, G. L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1421438111 · Cited by 460 · see citing works
Self-citationRetractedHIFs, angiogenesis, and metabolism: Elusive enemies in breast cancer
de Heer, E. C., Jalving, M., & Harris, A. L. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137552 · Cited by 372 · see citing works
Extracellular Metabolic Energetics Can Promote Cancer Progression
Loo, J. M., Scherl, A., Nguyen, A., Man, F. Y., Weinberg, E., Zeng, Z., Saltz, L., Paty, P. B., & Tavazoie, S. F. (2015) · Cell · doi:10.1016/j.cell.2014.12.018 · Cited by 393 · see citing works
A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment
Ohta, A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00109 · Cited by 385 · see citing works
NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer
Chio, I. I. C., Jafarnejad, S. M., Ponz-Sarvise, M., Park, Y., Rivera, K., Palm, W., Wilson, J., Sangar, V., Hao, Y., Öhlund, D., et al. (2016) · Cell · doi:10.1016/j.cell.2016.06.056 · Cited by 378 · see citing works
“Compromised Hif1a protein levels in KPn organoids corresponded with a decrease in the expression level of Hif1a target genes (Figure 5D), their inability to grow in hypoxia (Figure 5E), and heightened sensitivity to inhibition of glycolysis (Figure 5F) (Semenza, 2013).”
Structural integration in hypoxia-inducible factors
Wu, D., Potluri, N., Lu, J., Kim, Y., & Rastinejad, F. (2015) · Nature · doi:10.1038/nature14883 · Cited by 346 · see citing works
Anaemia in kidney disease: harnessing hypoxia responses for therapy
Koury, M. J., & Haase, V. H. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.82 · Cited by 313 · see citing works
Hoefflin, R., Harlander, S., Schäfer, S., Metzger, P., Kuo, F., Schönenberger, D., Adlesic, M., Peighambari, A., Seidel, P., Chen, C.-Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17873-3 · Cited by 292 · see citing works
Courtney, K. D., Bezwada, D., Mashimo, T., Pichumani, K., Vemireddy, V., Funk, A. M., Wimberly, J., McNeil, S. S., Kapur, P., Lotan, Y., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.07.020 · Cited by 280 · see citing works
Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer
Iommarini, L., Porcelli, A. M., Gasparre, G., & Kurelac, I. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00286 · Cited by 231 · see citing works
Zdzisińska, B., Żurek, A., & Kandefer-Szerszeń, M. (2017) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-016-0406-x · Cited by 221 · see citing works
Tumor hypoxia: From basic knowledge to therapeutic implications
Liao, C., Liu, X., Zhang, C., & Zhang, Q. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.12.011 · Cited by 223 · see citing works
Perl, A. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12756 · Cited by 218 · see citing works
Almendros, I., Wang, Y., Becker, L., Lennon, F. E., Zheng, J., Coats, B. R., Schoenfelt, K. S., Carreras, A., Hakim, F., Zhang, S. X., et al. (2014) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201310-1830oc · Cited by 201 · see citing works
Metabolic adaptation of cancer and immune cells mediated by hypoxia-inducible factors
Samanta, D., & Semenza, G. L. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.07.002 · Cited by 190 · see citing works
Self-citationPyruvate and metabolic flexibility: illuminating a path toward selective cancer therapies
Olson, K. A., Schell, J. C., & Rutter, J. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.01.002 · Cited by 154 · see citing works
Hyperthermia can alter tumor physiology and improve chemo- and radio-therapy efficacy
Dunne, M., Regenold, M., & Allen, C. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.07.007 · Cited by 150 · see citing works
Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance
Belisario, D. C., Kopecka, J., Pasino, M., Akman, M., De Smaele, E., Donadelli, M., & Riganti, C. (2020) · Cells · doi:10.3390/cells9122598 · Cited by 133 · see citing works
LncRNA IDH1-AS1 links the functions of c-Myc and HIF1α via IDH1 to regulate the Warburg effect
Xiang, S., Gu, H., Jin, L., Thorne, R. F., Zhang, X. D., & Wu, M. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1711257115 · Cited by 129 · see citing works
<i>IDH1</i> Mutation Induces Reprogramming of Pyruvate Metabolism
Izquierdo-Garcia, J. L., Viswanath, P., Eriksson, P., Cai, L., Radoul, M., Chaumeil, M. M., Blough, M., Luchman, H. A., Weiss, S., Cairncross, J. G., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0840 · Cited by 123 · see citing works
Sethumadhavan, S., Silva, M., Philbrook, P., Nguyen, T., Hatfield, S. M., Ohta, A., & Sitkovsky, M. V. (2017) · PLOS ONE · doi:10.1371/journal.pone.0187314 · Cited by 119 · see citing works
Hypoxia and the phenomenon of immune exclusion
Pietrobon, V., & Marincola, F. M. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-020-02667-4 · Cited by 119 · see citing works
Allison, K. E., Coomber, B. L., & Bridle, B. W. (2017) · Immunology · doi:10.1111/imm.12777 · Cited by 109 · see citing works
Hutt, D. M., Roth, D. M., Vignaud, H., Cullin, C., & Bouchecareilh, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106224 · Cited by 109 · see citing works
Kao, T.-W., Bai, G.-H., Wang, T.-L., Shih, I.-M., Chuang, C.-M., Lo, C.-L., Tsai, M.-C., Chiu, L.-Y., Lin, C.-C., & Shen, Y.-A. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02724-y · Cited by 89 · see citing works
Campbell, E. J., Vissers, M. C. M., Wohlrab, C., Hicks, K. O., Strother, R. M., Bozonet, S. M., Robinson, B. A., & Dachs, G. U. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.08.027 · Cited by 67 · see citing works
Campbell, E. J., Vissers, M. C. M., Bozonet, S., Dyer, A., Robinson, B. A., & Dachs, G. U. (2015) · Cancer Medicine · doi:10.1002/cam4.349 · Cited by 59 · see citing works
Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition
Li, C., Fu, C., Zhou, W., Li, H., Liu, Z., Wu, G., He, T., Shen, M., & Liu, H. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02366-x · Cited by 45 · see citing works
“In tumor-like, lactate-rich hypoxic environments, the stabilization of lactylated HIF-1α may potentiate glycolytic and pro-survival gene programs (e.g., VEGF and GLUT1), thereby enhancing metabolic adaptation, cell survival, and che-moresistance [43, 44].”
PPP2R5C couples hepatic glucose and lipid homeostasis
Cheng, Y.-S., Seibert, O., Klöting, N., Dietrich, A., Straßburger, K., Fernández-Veledo, S., Vendrell, J. J., Zorzano, A., Blüher, M., Herzig, S., et al. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005561 · Cited by 43 · see citing works
Tátrai, E., Bartal, A., Gacs, A., Paku, S., Kenessey, I., Garay, T., Hegedűs, B., Molnár, E., Cserepes, M. T., Hegedűs, Z., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.17806 · Cited by 33 · see citing works
Differential response to exercise in claudin-low breast cancer
Glass, O. K., Bowie, M., Fuller, J., Darr, D., Usary, J., Boss, K., Choudhury, K. R., Liu, X., Zhang, Z., Locasale, J. W., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.21054 · Cited by 32 · see citing works
Dal Molin, M., Brant, A., Blackford, A. L., Griffin, J. F., Shindo, K., Barkley, T., Rezaee, N., Hruban, R. H., Wolfgang, C. L., & Goggins, M. (2016) · PLOS ONE · doi:10.1371/journal.pone.0164195 · Cited by 19 · see citing works
HIF1α is not a target of 14q deletion in clear cell renal cancer
Shenoy, N. (2020) · Scientific Reports · doi:10.1038/s41598-020-74631-7 · Cited by 14 · see citing works
- Authors
- Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Semenza, Gregg L.
- ORCID
- Semenza, Gregg L.
- Venue
- Journal of Clinical Investigation
- Published
- 2013-09-03
- Volume
- 123
- Issue
- 9
- Pages
- 3664-3671
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3754249
- OpenAlex
- W1985458442
- Cited by
- 1,335
- References
- 26
- Citations by year
- 2026: 98 · 2025: 82 · 2024: 89 · 2023: 87 · 2022: 111 · 2021: 112 · 2020: 103 · 2019: 96 · 2018: 98 · 2017: 128 · 2016: 129 · 2015: 121 · 2014: 76 · 2013: 4 · 2012: 1
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W81XWH, W81XWH1210464)
- American Cancer Society
- Johns Hopkins University
- National Institutes of Health (W81XWH, CA143868)
- U.S. Public Health Service (HHS-N268201000032C)
- National Cancer Institute (U54CA143868)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- HIF-1, intratumoral hypoxia, cancer metabolism, metabolic reprogramming, glycolysis, oxidative phosphorylation, glutamine metabolism, fatty acid synthesis, PI3K/AKT/mTOR pathway, oncogenic mutations, tumor suppressor loss, treatment resistance, HIF-1 inhibitors
- MeSH terms
- Adaptation, Physiological, Animals, Energy Metabolism, Humans, Mutation, Neoplasms, Oncogenes, Cell Hypoxia, Drug Resistance, Neoplasm, Hypoxia-Inducible Factor 1, alpha Subunit
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