Skip to main content
SpringerLink
Log in
Book cover

Tumor Microenvironment and Cellular Stress pp 1–39Cite as

Hypoxia and Metabolism in Cancer

  • Conference paper
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 772))

Abstract

Interest in targeting metabolism has been renewed in recent years as research increases understanding of the altered metabolic profile of tumor cells compared with that of normal cells. Metabolic reprogramming allows cancer cells to survive and proliferate in the hostile tumor microenvironment. These metabolic changes support energy generation, anabolic processes, and the maintenance of redox potential, mechanisms that are all essential for the proliferation and survival of tumor cells. The metabolic switch in a number of key metabolic pathways is mainly regulated by genetic events, rendering cancer cells addicted to certain nutrients, such as glutamine. In addition, hypoxia is induced when highly proliferative tumor cells distance themselves from an oxygen supply. Hypoxia-inducible factor 1α is largely responsible for alterations in metabolism that support the survival of hypoxic tumor cells. Metabolic alterations and dependencies of cancer cells may be exploited to improve anticancer therapy. This chapter reviews the main aspects of altered metabolism in cancer cells, emphasizing recent advances in glucose, glutamine, and lipid metabolism.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Accioly MT, Pacheco P, Maya-Monteiro CM, Carrossini N, Robbs BK, Oliveira SS, Kaufmann C, Morgado-Diaz JA, Bozza PT, Viola JP (2008) Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells. Cancer Res 68(6):1732–1740, doi:68/6/1732 [pii] 10.1158/0008-5472.CAN-07-1999

    PubMed  CAS  Google Scholar 

  • Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M, Fischer R, Carmeliet P, Maxwell PH, Pugh CW, Frizzell N, Soga T, Kessler BM, El-Bahrawy M, Ratcliffe PJ, Pollard PJ (2011) Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20(4):524–537, doi:S1535-6108(11)00354-0 [pii] 10.1016/j.ccr.2011.09.006

    PubMed  CAS  Google Scholar 

  • Amary MF, Damato S, Halai D, Eskandarpour M, Berisha F, Bonar F, McCarthy S, Fantin VR, Straley KS, Lobo S, Aston W, Green CL, Gale RE, Tirabosco R, Futreal A, Campbell P, Presneau N, Flanagan AM (2011) Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet 43(12):1262–1265, doi:ng.994 [pii] 10.1038/ng.994

    PubMed  CAS  Google Scholar 

  • Amith SR, Fliegel L (2013) Regulation of the Na+/H+Exchanger (NHE1) in breast cancer metastasis. Cancer Res 73(4):1259–1264, doi:0008-5472.CAN-12-4031 [pii] 10.1158/0008-5472.CAN-12-4031

    PubMed  CAS  Google Scholar 

  • Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas CJ, Vander Heiden MG, Cantley LC (2011) Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334(6060):1278–1283, doi:science.1211485 [pii] 10.1126/science.1211485

    PubMed  CAS  Google Scholar 

  • Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A, Yang H, Mattaini KR, Metallo CM, Fiske BP, Courtney KD, Malstrom S, Khan TM, Kung C, Skoumbourdis AP, Veith H, Southall N, Walsh MJ, Brimacombe KR, Leister W, Lunt SY, Johnson ZR, Yen KE, Kunii K, Davidson SM, Christofk HR, Austin CP, Inglese J, Harris MH, Asara JM, Stephanopoulos G, Salituro FG, Jin S, Dang L, Auld DS, Park HW, Cantley LC, Thomas CJ, Vander Heiden MG (2012) Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 8(10):839–847, doi:nchembio.1060 [pii] 10.1038/nchembio.1060

    PubMed  CAS  Google Scholar 

  • Azam F, Mehta S, Harris AL (2010) Mechanisms of resistance to antiangiogenesis therapy. Eur J Cancer 46(8):1323–1332, doi:S0959-8049(10)00147-4 [pii] 10.1016/j.ejca.2010.02.020

    PubMed  CAS  Google Scholar 

  • Bardos JI, Ashcroft M (2004) Hypoxia-inducible factor-1 and oncogenic signalling. Bioessays 26(3):262–269. doi:10.1002/bies.20002

    PubMed  CAS  Google Scholar 

  • Bartrons R, Caro J (2007) Hypoxia, glucose metabolism and the Warburg’s effect. J Bioenerg Biomembr 39(3):223–229. doi:10.1007/s10863-007-9080-3

    PubMed  CAS  Google Scholar 

  • Bell EL, Emerling BM, Ricoult SJ, Guarente L (2011) SirT3 suppresses hypoxia inducible factor 1alpha and tumor growth by inhibiting mitochondrial ROS production. Oncogene 30(26):2986–2996, doi:onc201137 [pii] 10.1038/onc.2011.37

    PubMed  CAS  Google Scholar 

  • Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F (2008) The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27(25):3576–3586, doi:1211024 [pii] 10.1038/sj.onc.1211024

    PubMed  CAS  Google Scholar 

  • Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126(1):107–120, doi:S0092-8674(06)00762-8 [pii] 10.1016/j.cell.2006.05.036

    PubMed  CAS  Google Scholar 

  • Bensaad K, Cheung EC, Vousden KH (2009) Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J 28(19):3015–3026, doi:emboj2009242 [pii] 10.1038/emboj.2009.242

    PubMed  CAS  Google Scholar 

  • Bertout JA, Patel SA, Simon MC (2008) The impact of O2 availability on human cancer. Nat Rev Cancer 8(12):967–975, doi:nrc2540 [pii] 10.1038/nrc2540

    PubMed  CAS  Google Scholar 

  • Bluemlein K, Gruning NM, Feichtinger RG, Lehrach H, Kofler B, Ralser M (2011) No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis. Oncotarget 2(5):393–400, doi:278 [pii]

    PubMed  Google Scholar 

  • Bobarykina AY, Minchenko DO, Opentanova IL, Moenner M, Caro J, Esumi H, Minchenko OH (2006) Hypoxic regulation of PFKFB-3 and PFKFB-4 gene expression in gastric and pancreatic cancer cell lines and expression of PFKFB genes in gastric cancers. Acta Biochim Pol 53(4):789–799, doi:20061343 [pii]

    PubMed  CAS  Google Scholar 

  • Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11(1):37–51, doi:S1535-6108(06)00372-2 [pii] 10.1016/j.ccr.2006.10.020

    PubMed  CAS  Google Scholar 

  • Bozza PT, Viola JP (2010) Lipid droplets in inflammation and cancer. Prostaglandins Leukot Essent Fatty Acids 82(4–6):243–250, doi:S0952-3278(10)00049-9 [pii] 10.1016/j.plefa.2010.02.005

    PubMed  CAS  Google Scholar 

  • Bridges EM, Harris AL (2011) The angiogenic process as a therapeutic target in cancer. Biochem Pharmacol 81(10):1183–1191, doi:S0006-2952(11)00120-1 [pii] 10.1016/j.bcp.2011.02.0160

    PubMed  CAS  Google Scholar 

  • Brookheart RT, Michel CI, Schaffer JE (2009) As a matter of fat. Cell Metab 10(1):9–12, doi:S1550-4131(09)00089-8 [pii] 10.1016/j.cmet.2009.03.011

    PubMed  CAS  Google Scholar 

  • Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67(14):6745–6752, doi:67/14/6745 [pii] 10.1158/0008-5472.CAN-06-4447

    PubMed  CAS  Google Scholar 

  • Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85–95, doi:nrc2981 [pii] 10.1038/nrc2981

    PubMed  CAS  Google Scholar 

  • Caldwell SA, Jackson SR, Shahriari KS, Lynch TP, Sethi G, Walker S, Vosseller K, Reginato MJ (2010) Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene 29(19):2831–2842, doi:onc201041 [pii] 10.1038/onc.2010.41

    PubMed  CAS  Google Scholar 

  • Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 275(33):25130–25138. doi:10.1074/jbc.M001914200 M001914200 [pii]

    PubMed  CAS  Google Scholar 

  • Chaneton B, Hillmann P, Zheng L, Martin AC, Maddocks OD, Chokkathukalam A, Coyle JE, Jankevics A, Holding FP, Vousden KH, Frezza C, O’Reilly M, Gottlieb E (2012) Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491(7424):458–462, doi:nature11540 [pii] 10.1038/nature11540

    PubMed  CAS  Google Scholar 

  • Chen L, Endler A, Shibasaki F (2009) Hypoxia and angiogenesis: regulation of hypoxia-inducible factors via novel binding factors. Exp Mol Med 41(12):849–857. doi:10.3858/emm.2009.41.12.103

    PubMed  CAS  Google Scholar 

  • Chen H, Wang L, Beretov J, Hao J, Xiao W, Li Y (2010) Co-expression of CD147/EMMPRIN with monocarboxylate transporters and multiple drug resistance proteins is associated with epithelial ovarian cancer progression. Clin Exp Metastasis 27(8):557–569. doi:10.1007/s10585-010-9345-9

    PubMed  CAS  Google Scholar 

  • Cheong JH, Park ES, Liang J, Dennison JB, Tsavachidou D, Nguyen-Charles C, Wa Cheng K, Hall H, Zhang D, Lu Y, Ravoori M, Kundra V, Ajani J, Lee JS, Ki Hong W, Mills GB (2011) Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther 10(12):2350–2362, doi:1535-7163.MCT-11-0497 [pii] 10.1158/1535-7163.MCT-11-0497

    PubMed  CAS  Google Scholar 

  • Chiavarina B, Martinez-Outschoorn UE, Whitaker-Menezes D, Howell A, Tanowitz HB, Pestell RG, Sotgia F, Lisanti MP (2012) Metabolic reprogramming and two-compartment tumor metabolism: opposing role(s) of HIF1alpha and HIF2alpha in tumor-associated fibroblasts and human breast cancer cells. Cell Cycle 11(17):3280–3289, doi:21643 [pii] 10.4161/cc.21643

    PubMed  CAS  Google Scholar 

  • Chiche J, Brahimi-Horn MC, Pouyssegur J (2010) Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med 14(4):771–794, doi:JCMM994 [pii] 10.1111/j.1582-4934.2009.00994.x

    PubMed  CAS  Google Scholar 

  • Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008a) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452(7184):230–233, doi:nature06734 [pii] 10.1038/nature06734

    PubMed  CAS  Google Scholar 

  • Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC (2008b) Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452(7184):181–186, doi:nature06667 [pii] 10.1038/nature06667

    PubMed  CAS  Google Scholar 

  • Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, Rasku MA, Arumugam S, Dean WL, Eaton J, Lane A, Trent JO, Chesney J (2008) Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther 7(1):110–120, doi:7/1/110 [pii] 10.1158/1535-7163.MCT-07-0482

    PubMed  CAS  Google Scholar 

  • Dang CV (2012) Links between metabolism and cancer. Genes Dev 26(9):877–890, doi:26/9/877 [pii] 10.1101/gad.189365.112

    PubMed  CAS  Google Scholar 

  • Dang CV, Kim JW, Gao P, Yustein J (2008) The interplay between MYC and HIF in cancer. Nat Rev Cancer 8(1):51–56, doi:nrc2274 [pii] 10.1038/nrc2274

    PubMed  CAS  Google Scholar 

  • Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462(7274):739–744, doi:nature08617 [pii] 10.1038/nature08617

    PubMed  CAS  Google Scholar 

  • Daye D, Wellen KE (2012) Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol 23(4):362–369, doi:S1084-9521(12)00034-1 [pii] 10.1016/j.semcdb.2012.02.002

    PubMed  CAS  Google Scholar 

  • DeBerardinis RJ, Cheng T (2010) Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29(3):313–324, doi:onc2009358 [pii] 10.1038/onc.2009.358

    PubMed  CAS  Google Scholar 

  • DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104(49):19345–19350, doi:0709747104 [pii] 10.1073/pnas.0709747104

    PubMed  CAS  Google Scholar 

  • DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7(1):11–20, doi:S1550-4131(07)00295-1 [pii] 10.1016/j.cmet.2007.10.002

    PubMed  CAS  Google Scholar 

  • Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8(9):705–713. doi:10.1038/nrc2468

    PubMed  CAS  Google Scholar 

  • Diers AR, Broniowska KA, Chang CF, Hogg N (2012) Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition. Biochem J 444(3):561–571, doi:BJ20120294 [pii] 10.1042/BJ20120294

    PubMed  CAS  Google Scholar 

  • Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD, Garcia JA (2009) Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science 324(5932):1289–1293, doi:324/5932/1289 [pii] 10.1126/science.1169956

    PubMed  CAS  Google Scholar 

  • Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64(11):3892–3899, 10.1158/0008-5472.CAN-03-2904 64/11/3892 [pii]

    PubMed  CAS  Google Scholar 

  • Engel M, Mazurek S, Eigenbrodt E, Welter C (2004) Phosphoglycerate mutase-derived polypeptide inhibits glycolytic flux and induces cell growth arrest in tumor cell lines. J Biol Chem 279(34):35803–35812, doi:10.1074/jbc.M402768200 M402768200 [pii]

    PubMed  CAS  Google Scholar 

  • Evans JM, Ogston SA, Emslie-Smith A, Morris AD (2006) Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 49(5):930–936. doi:10.1007/s00125-006-0176-9

    PubMed  CAS  Google Scholar 

  • Faleck DM, Ali K, Roat R, Graham MJ, Crooke RM, Battisti R, Garcia E, Ahima RS, Imai Y (2010) Adipose differentiation-related protein regulates lipids and insulin in pancreatic islets. Am J Physiol Endocrinol Metab 299(2):E249–E257, doi:ajpendo.00646.2009 [pii] 10.1152/ajpendo.00646.2009

    PubMed  CAS  Google Scholar 

  • Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9(6):425–434, doi:S1535-6108(06)00145-0 [pii] 10.1016/j.ccr.2006.04.023

    PubMed  CAS  Google Scholar 

  • Farese RV Jr, Walther TC (2009) Lipid droplets finally get a little R-E-S-P-E-C-T. Cell 139(5):855–860, doi:S0092-8674(09)01417-2 [pii] 10.1016/j.cell.2009.11.005

    PubMed  CAS  Google Scholar 

  • Favaro E, Ramachandran A, McCormick R, Gee H, Blancher C, Crosby M, Devlin C, Blick C, Buffa F, Li JL, Vojnovic B, Piresdas Neves R, Glazer P, Iborra F, Ivan M, Ragoussis J, Harris 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. doi:10.1371/journal.pone.0010345

    PubMed  Google Scholar 

  • Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, Steers G, Turley H, Li JL, Gunther UL, Buffa FM, McIntyre A, Harris AL (2012) Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab. doi:S1550-4131(12)00451-2 [pii] 10.1016/j.cmet.2012.10.017

    PubMed  Google Scholar 

  • Fico A, Paglialunga F, Cigliano L, Abrescia P, Verde P, Martini G, Iaccarino I, Filosa S (2004) Glucose-6-phosphate dehydrogenase plays a crucial role in protection from redox-stress-induced apoptosis. Cell Death Differ 11(8):823–831. doi:10.1038/sj.cdd.4401420, 4401420 [pii]

    PubMed  CAS  Google Scholar 

  • Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Lowenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, Melnick A (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18(6):553–567, doi:S1535-6108(10)00483-6 [pii] 10.1016/j.ccr.2010.11.015

    Google Scholar 

  • Folger O, Jerby L, Frezza C, Gottlieb E, Ruppin E, Shlomi T (2011) Predicting selective drug targets in cancer through metabolic networks. Mol Syst Biol 7:501, doi:msb201135 [pii] 10.1038/msb.2011.35

    PubMed  Google Scholar 

  • Fritz V, Benfodda Z, Rodier G, Henriquet C, Iborra F, Avances C, Allory Y, de la Taille A, Culine S, Blancou H, Cristol JP, Michel F, Sardet C, Fajas L (2010) Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice. Mol Cancer Ther 9(6):1740–1754, doi:1535-7163.MCT-09-1064 [pii] 10.1158/1535-7163.MCT-09-1064

    PubMed  CAS  Google Scholar 

  • Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL (2007) HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129(1):111–122, doi:S0092-8674(07)00307-8 [pii] 10.1016/j.cell.2007.01.047

    PubMed  CAS  Google Scholar 

  • Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY, Hirota S, Hosobe S, Tsukada T, Miura K, Kamada S, Saito K, Iiizumi M, Liu W, Ericsson J, Watabe K (2008) Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 68(4):1003–1011, doi:68/4/1003 [pii] 10.1158/0008-5472.CAN-07-2489

    PubMed  CAS  Google Scholar 

  • Ganapathy-Kanniappan S, Vali M, Kunjithapatham R, Buijs M, Syed LH, Rao PP, Ota S, Kwak BK, Loffroy R, Geschwind JF (2010) 3-bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy. Curr Pharm Biotechnol 11(5):510–517, doi:BSP/CPB/E-Pub/0078-11-5 [pii]

    PubMed  CAS  Google Scholar 

  • Gao J, Serrero G (1999) Adipose differentiation related protein (ADRP) expressed in transfected COS-7 cells selectively stimulates long chain fatty acid uptake. J Biol Chem 274(24):16825–16830

    PubMed  CAS  Google Scholar 

  • Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239):762–765, doi:nature07823 [pii] 10.1038/nature07823

    PubMed  CAS  Google Scholar 

  • Gimm T, Wiese M, Teschemacher B, Deggerich A, Schodel J, Knaup KX, Hackenbeck T, Hellerbrand C, Amann K, Wiesener MS, Honing S, Eckardt KU, Warnecke C (2010) Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J 24(11):4443–4458, doi:fj.10-159806 [pii] 10.1096/fj.10-159806

    PubMed  CAS  Google Scholar 

  • Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC (2007) HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11(4):335–347, doi:S1535-6108(07)00059-1 [pii] 10.1016/j.ccr.2007.02.006

    PubMed  CAS  Google Scholar 

  • Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, Greenberg RA, Flaherty KT, Rathmell WK, Keith B, Simon MC, Nathanson KL (2008) HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14(6):435–446, doi:S1535-6108(08)00366-8 [pii] 10.1016/j.ccr.2008.10.016

    PubMed  CAS  Google Scholar 

  • Gottlieb E, Tomlinson IP (2005) Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5(11):857–866, doi:nrc1737 [pii] 10.1038/nrc1737

    PubMed  CAS  Google Scholar 

  • Gu Y, Mi W, Ge Y, Liu H, Fan Q, Han C, Yang J, Han F, Lu X, Yu W (2010) GlcNAcylation plays an essential role in breast cancer metastasis. Cancer Res 70(15):6344–6351, doi:0008-5472.CAN-09-1887 [pii] 10.1158/0008-5472.CAN-09-1887

    PubMed  CAS  Google Scholar 

  • Gupta SC, Hevia D, Patchva S, Park B, Koh W, Aggarwal BB (2012) Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid Redox Signal 16(11):1295–1322. doi:10.1089/ars.2011.4414

    PubMed  CAS  Google Scholar 

  • Guzy RD, Schumacker PT (2006) Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol 91(5):807–819, doi:expphysiol.2006.033506 [pii] 10.1113/expphysiol.2006.033506

    PubMed  CAS  Google Scholar 

  • Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT (2005) Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1(6):401–408, doi:S1550-4131(05)00139-7 [pii] 10.1016/j.cmet.2005.05.001

    PubMed  CAS  Google Scholar 

  • Guzy RD, Mack MM, Schumacker PT (2007) Mitochondrial complex III is required for hypoxia-induced ROS production and gene transcription in yeast. Antioxid Redox Signal 9(9):1317–1328. doi:10.1089/ars.2007.1708

    PubMed  CAS  Google Scholar 

  • Haigis MC, Yankner BA (2010) The aging stress response. Mol Cell 40(2):333–344, doi:S1097-2765(10)00778-1 [pii] 10.1016/j.molcel.2010.10.002

    PubMed  CAS  Google Scholar 

  • Halestrap AP, Wilson MC (2012) The monocarboxylate transporter family–role and regulation. IUBMB Life 64(2):109–119. doi:10.1002/iub.572

    PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70, doi:S0092-8674(00)81683-9 [pii]

    PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674, doi:S0092-8674(11)00127-9 [pii] 10.1016/j.cell.2011.02.013

    PubMed  CAS  Google Scholar 

  • Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262, doi:nrm3311 [pii] 10.1038/nrm3311

    PubMed  CAS  Google Scholar 

  • Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2(1):38–47. doi:10.1038/nrc704

    PubMed  CAS  Google Scholar 

  • Hess D, Chisholm JW, Igal RA (2010) Inhibition of stearoylCoA desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells. PLoS One 5(6):e11394. doi:10.1371/journal.pone.0011394

    PubMed  Google Scholar 

  • Hickey MM, Simon MC (2006) Regulation of angiogenesis by hypoxia and hypoxia-inducible factors. Curr Top Dev Biol 76:217–257, doi:S0070-2153(06)76007-0 [pii] 10.1016/S0070-2153(06)76007-0

    PubMed  CAS  Google Scholar 

  • Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69(19):7507–7511, doi:0008-5472.CAN-09-2994 [pii] 10.1158/0008-5472.CAN-09-2994

    PubMed  CAS  Google Scholar 

  • Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z (2010) Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci U S A 107(16):7455–7460, doi:1001006107 [pii] 10.1073/pnas.1001006107

    PubMed  CAS  Google Scholar 

  • Izaki S, Goto H, Yokota S (2008) Increased chemosensitivity and elevated reactive oxygen species are mediated by glutathione reduction in glutamine deprived neuroblastoma cells. J Cancer Res Clin Oncol 134(7):761–768. doi:10.1007/s00432-007-0338-2

    PubMed  CAS  Google Scholar 

  • Jensen KS, Binderup T, Jensen KT, Therkelsen I, Borup R, Nilsson E, Multhaupt H, Bouchard C, Quistorff B, Kjaer A, Landberg G, Staller P (2011) FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function. EMBO J 30(22):4554–4570, doi:emboj2011323 [pii] 10.1038/emboj.2011.323

    PubMed  CAS  Google Scholar 

  • Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, Yang X (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13(3):310–316, doi:ncb2172 [pii] 10.1038/ncb2172

    PubMed  CAS  Google Scholar 

  • Kilburn DG, Lilly MD, Webb FC (1969) The energetics of mammalian cell growth. J Cell Sci 4(3):645–654

    PubMed  CAS  Google Scholar 

  • Kim W, Liau LM (2012) IDH mutations in human glioma. Neurosurg Clin N Am 23(3):471–480, doi:S1042-3680(12)00048-4 [pii] 10.1016/j.nec.2012.04.009

    PubMed  Google Scholar 

  • Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006a) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177–185, doi:S1550-4131(06)00062-3 [pii] 10.1016/j.cmet.2006.02.002

    PubMed  Google Scholar 

  • Kim WY, Safran M, Buckley MR, Ebert BL, Glickman J, Bosenberg M, Regan M, Kaelin WG Jr (2006b) Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo. EMBO J 25(19):4650–4662, doi:7601300 [pii] 10.1038/sj.emboj.7601300

    PubMed  CAS  Google Scholar 

  • Kletzien RF, Harris PK, Foellmi LA (1994) Glucose-6-phosphate dehydrogenase: a “housekeeping” enzyme subject to tissue-specific regulation by hormones, nutrients, and oxidant stress. FASEB J 8(2):174–181

    PubMed  CAS  Google Scholar 

  • Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, Hullihen J, Pedersen PL (2004) Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 324(1):269–275, doi:S0006-291X(04)02062-5 [pii] 10.1016/j.bbrc.2004.09.047

    PubMed  CAS  Google Scholar 

  • Kobayashi S, Millhorn DE (2001) Hypoxia regulates glutamate metabolism and membrane transport in rat PC12 cells. J Neurochem 76(6):1935–1948

    PubMed  CAS  Google Scholar 

  • Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, Losman JA, Joensuu P, Bergmann U, Gross S, Travins J, Weiss S, Looper R, Ligon KL, Verhaak RG, Yan H, Kaelin WG Jr (2012) Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483(7390):484–488, doi:nature10898 [pii] 10.1038/nature10898

    PubMed  CAS  Google Scholar 

  • Kondoh H, Lleonart ME, Gil J, Wang J, Degan P, Peters G, Martinez D, Carnero A, Beach D (2005) Glycolytic enzymes can modulate cellular life span. Cancer Res 65(1):177–185, doi:65/1/177 [pii]

    PubMed  CAS  Google Scholar 

  • Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11(5):325–337, doi:nrc3038 [pii] 10.1038/nrc3038

    PubMed  CAS  Google Scholar 

  • Krishnan J, Suter M, Windak R, Krebs T, Felley A, Montessuit C, Tokarska-Schlattner M, Aasum E, Bogdanova A, Perriard E, Perriard JC, Larsen T, Pedrazzini T, Krek W (2009) Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab 9(6):512–524, doi:S1550-4131(09)00139-9 [pii] 10.1016/j.cmet.2009.05.005

    PubMed  CAS  Google Scholar 

  • Kwon SJ, Lee YJ (2005) Effect of low glutamine/glucose on hypoxia-induced elevation of hypoxia-inducible factor-1alpha in human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells. Clin Cancer Res 11(13):4694–4700, doi:11/13/4694 [pii] 10.1158/1078-0432.CCR-04-2530

    PubMed  CAS  Google Scholar 

  • Laemmle A, Lechleiter A, Roh V, Schwarz C, Portmann S, Furer C, Keogh A, Tschan MP, Candinas D, Vorburger SA, Stroka D (2012) Inhibition of SIRT1 impairs the accumulation and transcriptional activity of HIF-1alpha protein under hypoxic conditions. PLoS One 7(3):e33433, doi:10.1371/journal.pone.0033433 PONE-D-12-00867 [pii]

    PubMed  CAS  Google Scholar 

  • Laurenti G, Benedetti E, D’Angelo B, Cristiano L, Cinque B, Raysi S, Alecci M, Ceru MP, Cifone MG, Galzio R, Giordano A, Cimini A (2011) Hypoxia induces peroxisome proliferator-activated receptor alpha (PPARalpha) and lipid metabolism peroxisomal enzymes in human glioblastoma cells. J Cell Biochem 112(12):3891–3901. doi:10.1002/jcb.23323

    PubMed  CAS  Google Scholar 

  • Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV (2010) Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A 107(5):2037–2042, doi:0914433107 [pii] 10.1073/pnas.0914433107

    PubMed  CAS  Google Scholar 

  • Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos RJ, Lorkiewicz PK, Higashi RM, Fan TW, Dang CV (2012) Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 15(1):110–121, doi:S1550-4131(11)00468-2 [pii] 10.1016/j.cmet.2011.12.009

    PubMed  CAS  Google Scholar 

  • Levine AJ, Puzio-Kuter AM (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330(6009):1340–1344, doi:330/6009/1340 [pii] 10.1126/science.1193494

    PubMed  CAS  Google Scholar 

  • Li J, Ding SF, Habib NA, Fermor BF, Wood CB, Gilmour RS (1994) Partial characterization of a cDNA for human stearoyl-CoA desaturase and changes in its mRNA expression in some normal and malignant tissues. Int J Cancer 57(3):348–352

    PubMed  CAS  Google Scholar 

  • Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O’Donnell KA, Kim JW, Yustein JT, Lee LA, Dang CV (2005) Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25(14):6225–6234, doi:25/14/6225 [pii] 10.1128/MCB.25.14.6225-6234.2005

    PubMed  CAS  Google Scholar 

  • Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW (2010) Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell 38(6):864–878, doi:S1097-2765(10)00385-0 [pii] 10.1016/j.molcel.2010.05.023

    PubMed  CAS  Google Scholar 

  • Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE (2003) Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 100(6):3077–3082, doi:10.1073/pnas.0630588100 0630588100 [pii]

    PubMed  CAS  Google Scholar 

  • Liu Y (2006) Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer Prostatic Dis 9(3):230–234, doi:4500879 [pii] 10.1038/sj.pcan.4500879

    PubMed  CAS  Google Scholar 

  • Liu K, Czaja MJ (2013) Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ 20(1):3–11, doi:cdd201263 [pii] 10.1038/cdd.2012.63

    PubMed  CAS  Google Scholar 

  • Locasale JW, Cantley LC (2011) Metabolic flux and the regulation of mammalian cell growth. Cell Metab 14(4):443–451, doi:S1550-4131(11)00345-7 [pii] 10.1016/j.cmet.2011.07.014

    PubMed  CAS  Google Scholar 

  • Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, Vander Heiden MG (2011) Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 43(9):869–874, doi:ng.890 [pii] 10.1038/ng.890

    Google Scholar 

  • Loo SY, Chang MK, Chua CS, Kumar AP, Pervaiz S, Clement MV (2012) NHE-1: a promising target for novel anti-cancer therapeutics. Curr Pharm Des 18(10):1372–1382, doi:CPD-EPUB-20120223-002 [pii]

    PubMed  Google Scholar 

  • Losman JA, Looper R, Koivunen P, Lee S, Schneider RK, McMahon C, Cowley G, Root D, Ebert BL, Kaelin WG Jr (2013) (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. doi:doi:science.1231677 [pii] 10.1126/science.1231677

    PubMed  Google Scholar 

  • Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O’Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, Thompson CB (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483(7390):474–478, doi:nature10860 [pii] 10.1038/nature10860

    PubMed  CAS  Google Scholar 

  • Luo W, Semenza GL (2011) Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget 2(7):551–556, doi:299 [pii]

    PubMed  Google Scholar 

  • Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145(5):732–744, doi:S0092-8674(11)00436-3 [pii] 10.1016/j.cell.2011.03.054

    PubMed  CAS  Google Scholar 

  • Maddocks OD, Vousden KH (2011) Metabolic regulation by p53. J Mol Med (Berl) 89(3):237–245. doi:10.1007/s00109-011-0735-5

    CAS  Google Scholar 

  • Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH (2013) Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493(7433):542–546, doi:nature11743 [pii] 10.1038/nature11743

    PubMed  CAS  Google Scholar 

  • Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) p53 regulates mitochondrial respiration. Science 312(5780):1650–1653, doi:1126863 [pii] 10.1126/science.1126863

    PubMed  CAS  Google Scholar 

  • Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7(10):763–777, doi:nrc2222 [pii] 10.1038/nrc2222

    PubMed  CAS  Google Scholar 

  • Mera P, Bentebibel A, Lopez-Vinas E, Cordente AG, Gurunathan C, Sebastian D, Vazquez I, Herrero L, Ariza X, Gomez-Puertas P, Asins G, Serra D, Garcia J, Hegardt FG (2009) C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight. Biochem Pharmacol 77(6):1084–1095, doi:S0006-2952(08)00855-1 [pii] 10.1016/j.bcp.2008.11.020

    PubMed  CAS  Google Scholar 

  • Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G (2011) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481(7381):380–384, doi:nature10602 [pii] 10.1038/nature10602

    PubMed  Google Scholar 

  • Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC (2010) Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2(31):31ra34, doi:2/31/31ra34 [pii] 10.1126/scitranslmed.3000677

    PubMed  CAS  Google Scholar 

  • Minamishima YA, Moslehi J, Padera RF, Bronson RT, Liao R, Kaelin WG Jr (2009) A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Mol Cell Biol 29(21):5729–5741, doi:MCB.00331-09 [pii] 10.1128/MCB.00331-09

    PubMed  CAS  Google Scholar 

  • Minchenko OH, Opentanova IL, Ogura T, Minchenko DO, Komisarenko SV, Caro J, Esumi H (2005) Expression and hypoxia-responsiveness of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 in mammary gland malignant cell lines. Acta Biochim Pol 52(4):881–888, doi:20051025 [pii]

    PubMed  CAS  Google Scholar 

  • Morrish F, Isern N, Sadilek M, Jeffrey M, Hockenbery DM (2009) c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry. Oncogene 28(27):2485–2491, doi:onc2009112 [pii] 10.1038/onc.2009.112

    PubMed  CAS  Google Scholar 

  • Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ (2011) Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481(7381):385–388, doi:nature10642 [pii] 10.1038/nature10642

    PubMed  Google Scholar 

  • Murdoch C, Muthana M, Lewis CE (2005) Hypoxia regulates macrophage functions in inflammation. J Immunol 175(10):6257–6263, doi:175/10/6257 [pii]

    PubMed  CAS  Google Scholar 

  • Mylonis I, Sembongi H, Befani C, Liakos P, Siniossoglou S, Simos G (2012) Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression. J Cell Sci 125(Pt 14):3485–3493, doi:jcs.106682 [pii] 10.1242/jcs.106682

    PubMed  CAS  Google Scholar 

  • Narravula S, Colgan SP (2001) Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor alpha expression during hypoxia. J Immunol 166(12):7543–7548

    PubMed  CAS  Google Scholar 

  • Nishiyama Y, Goda N, Kanai M, Niwa D, Osanai K, Yamamoto Y, Senoo-Matsuda N, Johnson RS, Miura S, Kabe Y, Suematsu M (2012) HIF-1alpha induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice. J Hepatol 56(2):441–447, doi:S0168-8278(11)00659-3 [pii] 10.1016/j.jhep.2011.07.024

    PubMed  CAS  Google Scholar 

  • Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF (2010) Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140(1):49–61, doi:S0092-8674(09)01439-1 [pii] 10.1016/j.cell.2009.11.027

    PubMed  CAS  Google Scholar 

  • Obach M, Navarro-Sabate A, Caro J, Kong X, Duran J, Gomez M, Perales JC, Ventura F, Rosa JL, Bartrons R (2004) 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia. J Biol Chem 279(51):53562–53570, doi:M406096200 [pii] 10.1074/jbc.M406096200

    PubMed  CAS  Google Scholar 

  • Oktay Y, Dioum E, Matsuzaki S, Ding K, Yan LJ, Haller RG, Szweda LI, Garcia JA (2007) Hypoxia-inducible factor 2alpha regulates expression of the mitochondrial aconitase chaperone protein frataxin. J Biol Chem 282(16):11750–11756, doi:M611133200 [pii] 10.1074/jbc.M611133200

    PubMed  CAS  Google Scholar 

  • Pan Y, Mansfield KD, Bertozzi CC, Rudenko V, Chan DA, Giaccia AJ, Simon MC (2007) Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Mol Cell Biol 27(3):912–925, doi:MCB.01223-06 [pii] 10.1128/MCB.01223-06

    PubMed  CAS  Google Scholar 

  • Pandey PR, Liu W, Xing F, Fukuda K, Watabe K (2012) Anti-cancer drugs targeting fatty acid synthase (FAS). Recent Pat Anticancer Drug Discov 7(2):185–197, doi:PRA-EPUB-20120209-002 [pii]

    PubMed  CAS  Google Scholar 

  • Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3(3):187–197, doi:S1550-4131(06)00060-X [pii] 10.1016/j.cmet.2006.01.012

    PubMed  CAS  Google Scholar 

  • Patel SA, Simon MC (2008) Biology of hypoxia-inducible factor-2 alpha in development and disease. Cell Death Differ 15(4):628–634, doi:cdd200817 [pii] 10.1038/cdd.2008.17

    PubMed  CAS  Google Scholar 

  • Pelicano H, Martin DS, Xu RH, Huang P (2006) Glycolysis inhibition for anticancer treatment. Oncogene 25(34):4633–4646, doi:1209597 [pii] 10.1038/sj.onc.1209597

    PubMed  CAS  Google Scholar 

  • Pike LS, Smift AL, Croteau NJ, Ferrick DA, Wu M (2010) Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim Biophys Acta, doi:S0005-2728(10)00740-1 [pii] 10.1016/j.bbabio.2010.10.022

  • Pinheiro C, Longatto-Filho A, Simoes K, Jacob CE, Bresciani CJ, Zilberstein B, Cecconello I, Alves VA, Schmitt F, Baltazar F (2009) The prognostic value of CD147/EMMPRIN is associated with monocarboxylate transporter 1 co-expression in gastric cancer. Eur J Cancer 45(13):2418–2424, doi:S0959-8049(09)00485-7 [pii] 10.1016/j.ejca.2009.06.018

    PubMed  CAS  Google Scholar 

  • Pinheiro C, Albergaria A, Paredes J, Sousa B, Dufloth R, Vieira D, Schmitt F, Baltazar F (2010) Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma. Histopathology 56(7):860–867, doi:HIS3560 [pii] 10.1111/j.1365-2559.2010.03560.x

    PubMed  Google Scholar 

  • Pollari S, Kakonen SM, Edgren H, Wolf M, Kohonen P, Sara H, Guise T, Nees M, Kallioniemi O (2011) Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat 125(2):421–430. doi:10.1007/s10549-010-0848-5

    PubMed  CAS  Google Scholar 

  • Porporato PE, Dhup S, Dadhich RK, Copetti T, Sonveaux P (2011) Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol 2:49. doi:10.3389/fphar.2011.00049

    PubMed  Google Scholar 

  • Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM (2011) Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476(7360):346–350, doi:nature10350 [pii] 10.1038/nature10350

    PubMed  CAS  Google Scholar 

  • Prabhakar NR, Kumar GK, Nanduri J (2010) Intermittent hypoxia augments acute hypoxic sensing via HIF-mediated ROS. Respir Physiol Neurobiol 174(3):230–234, doi:S1569-9048(10)00326-5 [pii] 10.1016/j.resp.2010.08.022

    PubMed  CAS  Google Scholar 

  • Puskas LG, Feher LZ, Vizler C, Ayaydin F, Raso E, Molnar E, Magyary I, Kanizsai I, Gyuris M, Madacsi R, Fabian G, Farkas K, Hegyi P, Baska F, Ozsvari B, Kitajka K (2010) Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells. Lipids Health Dis 9:56, doi:1476-511X-9-56 [pii] 10.1186/1476-511X-9-56

    PubMed  Google Scholar 

  • Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11(11):761–774, doi:nrc3106 [pii] 10.1038/nrc3106

    PubMed  CAS  Google Scholar 

  • Qing G, Skuli N, Mayes PA, Pawel B, Martinez D, Maris JM, Simon MC (2010) Combinatorial regulation of neuroblastoma tumor progression by N-Myc and hypoxia inducible factor HIF-1alpha. Cancer Res 70(24):10351–10361, doi:0008-5472.CAN-10-0740 [pii] 10.1158/0008-5472.CAN-10-0740

    PubMed  CAS  Google Scholar 

  • Rademakers SE, Lok J, van der Kogel AJ, Bussink J, Kaanders JH (2011) Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1alpha, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer 11:167, doi:1471-2407-11-167 [pii] 10.1186/1471-2407-11-167

    PubMed  Google Scholar 

  • Rakheja D, Konoplev S, Medeiros LJ, Chen W (2012) IDH mutations in acute myeloid leukemia. Hum Pathol 43(10):1541–1551, doi:S0046-8177(12)00165-7 [pii] 10.1016/j.humpath.2012.05.003

    PubMed  CAS  Google Scholar 

  • Rankin EB, Rha J, Selak MA, Unger TL, Keith B, Liu Q, Haase VH (2009) Hypoxia-inducible factor 2 regulates hepatic lipid metabolism. Mol Cell Biol 29(16):4527–4538, doi:MCB.00200-09 [pii] 10.1128/MCB.00200-09

    PubMed  CAS  Google Scholar 

  • Rey S, Semenza GL (2010) Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 86(2):236–242, doi:cvq045 [pii] 10.1093/cvr/cvq045

    PubMed  CAS  Google Scholar 

  • Rios EJ, Fallon M, Wang J, Shimoda LA (2005) Chronic hypoxia elevates intracellular pH and activates Na+/H+ exchange in pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 289(5):L867–L874, doi:00455.2004 [pii] 10.1152/ajplung.00455.2004

    PubMed  CAS  Google Scholar 

  • Robey RB, Hay N (2009) Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol 19(1):25–31, doi:S1044-579X(08)00105-3 [pii] 10.1016/j.semcancer.2008.11.010

    PubMed  CAS  Google Scholar 

  • Roy S, Ghosh S, Mallick P, Maity P (2008) Acivicin with glutaminase regulates proliferation and invasion of human MCF-7 and OAW-42 cells–an in vitro study. Indian J Exp Biol 46(1):22–26

    PubMed  CAS  Google Scholar 

  • Rysman E, Brusselmans K, Scheys K, Timmermans L, Derua R, Munck S, Van Veldhoven PP, Waltregny D, Daniels VW, Machiels J, Vanderhoydonc F, Smans K, Waelkens E, Verhoeven G, Swinnen JV (2010) De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res 70(20):8117–8126, doi:0008-5472.CAN-09-3871 [pii] 10.1158/0008-5472.CAN-09-3871

    PubMed  CAS  Google Scholar 

  • Saarikoski ST, Rivera SP, Hankinson O (2002) Mitogen-inducible gene 6 (MIG-6), adipophilin and tuftelin are inducible by hypoxia. FEBS Lett 530(1–3):186–190, doi:S0014579302034750 [pii]

    PubMed  CAS  Google Scholar 

  • Salem AF, Whitaker-Menezes D, Lin Z, Martinez-Outschoorn UE, Tanowitz HB, Al-Zoubi MS, Howell A, Pestell RG, Sotgia F, Lisanti MP (2012) Two-compartment tumor metabolism: autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells. Cell Cycle 11(13):2545–2556, doi:20920 [pii] 10.4161/cc.20920

    PubMed  CAS  Google Scholar 

  • Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, Kaluarachchi K, Bornmann W, Duvvuri S, Taegtmeyer H, Andreeff M (2010) Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest 120(1):142–156, doi:38942 [pii] 10.1172/JCI38942

    PubMed  CAS  Google Scholar 

  • Santos CR, Schulze A (2012) Lipid metabolism in cancer. FEBS J 279(15):2610–2623. doi:10.1111/j.1742-4658.2012.08644.x

    PubMed  CAS  Google Scholar 

  • Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brustle A, Harris IS, Holmes R, Wakeham A, Haight J, You-Ten A, Li WY, Schalm S, Su SM, Virtanen C, Reifenberger G, Ohashi PS, Barber DL, Figueroa ME, Melnick A, Zuniga-Pflucker JC, Mak TW (2012) IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488(7413):656–659, doi:nature11323 [pii] 10.1038/nature11323

    PubMed  CAS  Google Scholar 

  • Scaglia N, Caviglia JM, Igal RA (2005) High stearoyl-CoA desaturase protein and activity levels in simian virus 40 transformed-human lung fibroblasts. Biochim Biophys Acta 1687(1–3):141–151, doi:S1388-1981(04)00199-4 [pii] 10.1016/j.bbalip.2004.11.015

    PubMed  CAS  Google Scholar 

  • Scaglia N, Chisholm JW, Igal RA (2009) Inhibition of stearoylCoA desaturase-1 inactivates acetyl-CoA carboxylase and impairs proliferation in cancer cells: role of AMPK. PLoS One 4(8):e6812. doi:10.1371/journal.pone.0006812

    PubMed  Google Scholar 

  • Schonfeld P, Wojtczak L (2008) Fatty acids as modulators of the cellular production of reactive oxygen species. Free Radic Biol Med 45(3):231–241, doi:S0891-5849(08)00250-5 [pii] 10.1016/j.freeradbiomed.2008.04.029

    PubMed  Google Scholar 

  • Schug TT, Li X (2011) Sirtuin 1 in lipid metabolism and obesity. Ann Med 43(3):198–211, 10.3109/07853890.2010.547211

    PubMed  CAS  Google Scholar 

  • Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E (2004) The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 64(7): 2627–2633

    PubMed  CAS  Google Scholar 

  • Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan LJ, Marck BT, Matsumoto AM, Shelton JM, Richardson JA, Bennett MJ, Garcia JA (2003) Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice. Nat Genet 35(4):331–340, doi:10.1038/ng1266ng1266 [pii]

    PubMed  CAS  Google Scholar 

  • Sears R, Leone G, DeGregori J, Nevins JR (1999) Ras enhances Myc protein stability. Mol Cell 3(2):169–179, doi:S1097-2765(00)80308-1 [pii]

    PubMed  CAS  Google Scholar 

  • Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, Tsukamoto T, Rojas CJ, Slusher BS, Rabinowitz JD, Dang CV, Riggins GJ (2010) Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res 70(22):8981–8987, doi:0008-5472.CAN-10-1666 [pii] 10.1158/0008-5472.CAN-10-1666

    PubMed  CAS  Google Scholar 

  • Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29(5):625–634, doi:onc2009441 [pii] 10.1038/onc.2009.441

    PubMed  CAS  Google Scholar 

  • Semenza GL (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci 33(4):207–214, doi:S0165-6147(12)00017-X [pii] 10.1016/j.tips.2012.01.005

    PubMed  CAS  Google Scholar 

  • Semenza GL, Roth PH, Fang HM, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269(38):23757–23763

    PubMed  CAS  Google Scholar 

  • Shen GM, Zhao YZ, Chen MT, Zhang FL, Liu XL, Wang Y, Liu CZ, Yu J, Zhang JW (2010) Hypoxia-inducible factor-1 (HIF-1) promotes LDL and VLDL uptake through inducing VLDLR under hypoxia. Biochem J 441(2):675–683, doi:BJ20111377 [pii] 10.1042/BJ20111377

    Google Scholar 

  • Shi Y, Tomic J, Wen F, Shaha S, Bahlo A, Harrison R, Dennis JW, Williams R, Gross BJ, Walker S, Zuccolo J, Deans JP, Hart GW, Spaner DE (2010) Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia. Leukemia 24(9):1588–1598, doi:leu2010152 [pii] 10.1038/leu.2010.152

    PubMed  CAS  Google Scholar 

  • Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, Dalla-Favera R, Dang CV (1997) c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci U S A 94(13):6658–6663

    PubMed  CAS  Google Scholar 

  • Shimoda LA, Fallon M, Pisarcik S, Wang J, Semenza GL (2006) HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 291(5):L941–L949, doi:00528.2005 [pii] 10.1152/ajplung.00528.2005

    PubMed  CAS  Google Scholar 

  • Singh R, Cuervo AM (2012) Lipophagy: connecting autophagy and lipid metabolism. Int J Cell Biol 2012:282041. doi:10.1155/2012/282041

    PubMed  Google Scholar 

  • Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458(7242):1131–1135, doi:nature07976 [pii] 10.1038/nature07976

    PubMed  CAS  Google Scholar 

  • Smeland TE, Nada M, Cuebas D, Schulz H (1992) NADPH-dependent beta-oxidation of unsaturated fatty acids with double bonds extending from odd-numbered carbon atoms. Proc Natl Acad Sci U S A 89(15):6673–6677

    PubMed  CAS  Google Scholar 

  • Soh H, Wasa M, Fukuzawa M (2007) Hypoxia upregulates amino acid transport in a human neuroblastoma cell line. J Pediatr Surg 42(4):608–612, doi:S0022-3468(06)00940-7 [pii] 10.1016/j.jpedsurg.2006.12.010

    PubMed  Google Scholar 

  • Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S, Lisanti MP (2012) Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol 7:423–467. doi:10.1146/annurev-pathol-011811-120856

    PubMed  CAS  Google Scholar 

  • Stambolsky P, Weisz L, Shats I, Klein Y, Goldfinger N, Oren M, Rotter V (2006) Regulation of AIF expression by p53. Cell Death Differ 13(12):2140–2149, doi:4401965 [pii] 10.1038/sj.cdd.4401965

    PubMed  CAS  Google Scholar 

  • Su X, Abumrad NA (2009) Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab 20(2):72–77, doi:S1043-2760(09)00003-4 [pii] 10.1016/j.tem.2008.11.001

    PubMed  CAS  Google Scholar 

  • Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, Sugano S, Sato E, Nagao T, Yokote K, Tatsuno I, Prives C (2010) Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A 107(16):7461–7466, doi:1002459107 [pii] 10.1073/pnas.1002459107

    PubMed  CAS  Google Scholar 

  • Swinnen JV, Brusselmans K, Verhoeven G (2006) Increased lipogenesis in cancer cells: new players, novel targets. Curr Opin Clin Nutr Metab Care 9(4):358–365, doi:10.1097/01.mco.0000232894.28674.30, 00075197-200607000-00005 [pii]

    PubMed  CAS  Google Scholar 

  • Tamura K, Makino A, Hullin-Matsuda F, Kobayashi T, Furihata M, Chung S, Ashida S, Miki T, Fujioka T, Shuin T, Nakamura Y, Nakagawa H (2009) Novel lipogenic enzyme ELOVL7 is involved in prostate cancer growth through saturated long-chain fatty acid metabolism. Cancer Res 69(20):8133–8140, doi:0008-5472.CAN-09-0775 [pii] 10.1158/0008-5472.CAN-09-0775

    PubMed  CAS  Google Scholar 

  • Tan EY, Yan M, Campo L, Han C, Takano E, Turley H, Candiloro I, Pezzella F, Gatter KC, Millar EK, O’Toole SA, McNeil CM, Crea P, Segara D, Sutherland RL, Harris AL, Fox SB (2009) The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy. Br J Cancer 100(2):405–411, doi:6604844 [pii] 10.1038/sj.bjc.6604844

    PubMed  CAS  Google Scholar 

  • Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordonez A, Corral-Escariz M, Soro I, Lopez-Bernardo E, Perales-Clemente E, Martinez-Ruiz A, Enriquez JA, Aragones J, Cadenas S, Landazuri MO (2011) Induction of the mitochondrial NDUFA4L2 protein by HIF-1alpha decreases oxygen consumption by inhibiting complex I activity. Cell Metab 14(6):768–779, doi:S1550-4131(11)00394-9 [pii] 10.1016/j.cmet.2011.10.008

    PubMed  CAS  Google Scholar 

  • Tian WN, Braunstein LD, Apse K, Pang J, Rose M, Tian X, Stanton RC (1999) Importance of glucose-6-phosphate dehydrogenase activity in cell death. Am J Physiol 276(5 Pt 1):C1121–C1131

    PubMed  CAS  Google Scholar 

  • Ullah MS, Davies AJ, Halestrap AP (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem 281(14):9030–9037, doi:M511397200 [pii] 10.1074/jbc.M511397200

    PubMed  CAS  Google Scholar 

  • Vander Heiden MG (2011) Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10(9):671–684, doi:nrd3504 [pii] 10.1038/nrd3504

    PubMed  CAS  Google Scholar 

  • Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033, doi:324/5930/1029 [pii] 10.1126/science.1160809

    PubMed  CAS  Google Scholar 

  • Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, Cantley LC (2010) Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329(5998):1492–1499, doi:329/5998/1492 [pii] 10.1126/science.1188015

    PubMed  CAS  Google Scholar 

  • Vousden KH, Ryan KM (2009) p53 and metabolism. Nat Rev Cancer 9(10):691–700, doi:nrc2715 [pii] 10.1038/nrc2715

    PubMed  CAS  Google Scholar 

  • Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA (2010a) Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18(3):207–219, doi:S1535-6108(10)00306-5 [pii] 10.1016/j.ccr.2010.08.009

    PubMed  CAS  Google Scholar 

  • Wang C, Rajput S, Watabe K, Liao DF, Cao D (2010b) Acetyl-CoA carboxylase-a as a novel target for cancer therapy. Front Biosci (Schol Ed) 2:515–526, doi:82 [pii]

    Google Scholar 

  • Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    PubMed  CAS  Google Scholar 

  • Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17(3):225–234, doi:S1535-6108(10)00036-X [pii] 10.1016/j.ccr.2010.01.020

    PubMed  CAS  Google Scholar 

  • Wellen KE, Lu C, Mancuso A, Lemons JM, Ryczko M, Dennis JW, Rabinowitz JD, Coller HA, Thompson CB (2010) The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev 24(24):2784–2799, doi:gad.1985910 [pii] 10.1101/gad.1985910

    PubMed  CAS  Google Scholar 

  • Whitmer JT, Idell-Wenger JA, Rovetto MJ, Neely JR (1978) Control of fatty acid metabolism in ischemic and hypoxic hearts. J Biol Chem 253(12):4305–4309

    PubMed  CAS  Google Scholar 

  • Wise DR, Thompson CB (2010) Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 35(8):427–433, doi:S0968-0004(10)00091-5 [pii] 10.1016/j.tibs.2010.05.003

    PubMed  CAS  Google Scholar 

  • Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A 105(48):18782–18787, doi:0810199105 [pii] 10.1073/pnas.0810199105

    PubMed  CAS  Google Scholar 

  • Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, Platt JM, DeMatteo RG, Simon MC, Thompson CB (2011) Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A 108(49):19611–19616, doi:1117773108 [pii] 10.1073/pnas.1117773108

    PubMed  CAS  Google Scholar 

  • Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60(24):7075–7083

    PubMed  CAS  Google Scholar 

  • Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19(1):17–30, doi:S1535-6108(10)00527-1 [pii] 10.1016/j.ccr.2010.12.014

    PubMed  CAS  Google Scholar 

  • Yalcin A, Telang S, Clem B, Chesney J (2009) Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer. Exp Mol Pathol 86(3):174–179, doi:S0014-4800(09)00008-2 [pii] 10.1016/j.yexmp.2009.01.003

    PubMed  CAS  Google Scholar 

  • Ye J, Mancuso A, Tong X, Ward PS, Fan J, Rabinowitz JD, Thompson CB (2012) Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc Natl Acad Sci U S A 109(18):6904–6909, doi:1204176109 [pii] 10.1073/pnas.1204176109

    PubMed  CAS  Google Scholar 

  • Yoshii Y, Furukawa T, Yoshii H, Mori T, Kiyono Y, Waki A, Kobayashi M, Tsujikawa T, Kudo T, Okazawa H, Yonekura Y, Fujibayashi Y (2009) Cytosolic acetyl-CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl-CoA/acetate metabolism. Cancer Sci 100(5):821–827

    PubMed  CAS  Google Scholar 

  • Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M (2006) Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66(21):10269–10273, doi:0008-5472.CAN-06-1500 [pii] 10.1158/0008-5472.CAN-06-1500

    PubMed  CAS  Google Scholar 

  • Zaugg K, Yao Y, Reilly PT, Kannan K, Kiarash R, Mason J, Huang P, Sawyer SK, Fuerth B, Faubert B, Kalliomaki T, Elia A, Luo X, Nadeem V, Bungard D, Yalavarthi S, Growney JD, Wakeham A, Moolani Y, Silvester J, Ten AY, Bakker W, Tsuchihara K, Berger SL, Hill RP, Jones RG, Tsao M, Robinson MO, Thompson CB, Pan G, Mak TW (2011) Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev 25(10):1041–1051, doi:25/10/1041 [pii] 10.1101/gad.1987211

    PubMed  CAS  Google Scholar 

  • Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11(5):407–420, doi:S1535-6108(07)00115-8 [pii] 10.1016/j.ccr.2007.04.001

    PubMed  CAS  Google Scholar 

  • Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283(16):10892–10903, doi:M800102200 [pii] 10.1074/jbc.M800102200

    PubMed  CAS  Google Scholar 

  • Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, Soh BS, Sun LL, Tai BC, Nga ME, Bhakoo KK, Jayapal SR, Nichane M, Yu Q, Ahmed DA, Tan C, Sing WP, Tam J, Thirugananam A, Noghabi MS, Pang YH, Ang HS, Mitchell W, Robson P, Kaldis P, Soo RA, Swarup S, Lim EH, Lim B (2012) Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148(1–2):259–272, doi:S0092-8674(11)01444-9 [pii] 10.1016/j.cell.2011.11.050

    PubMed  CAS  Google Scholar 

  • Zhao F, Mancuso A, Bui TV, Tong X, Gruber JJ, Swider CR, Sanchez PV, Lum JJ, Sayed N, Melo JV, Perl AE, Carroll M, Tuttle SW, Thompson CB (2010) Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1alpha-induced metabolic reprograming. Oncogene 29(20):2962–2972, doi:onc201067 [pii] 10.1038/onc.2010.67

    PubMed  CAS  Google Scholar 

  • Zoula S, Rijken PF, Peters JP, Farion R, Van der Sanden BP, Van der Kogel AJ, Decorps M, Remy C (2003) Pimonidazole binding in C6 rat brain glioma: relation with lipid droplet detection. Br J Cancer 88(9):1439–1444, doi:10.1038/sj.bjc.6600837 6600837 [pii]

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank E. Favaro and A. McIntyre for their critical reading and feedback. K.B. is supported by a Cancer Research UK fellowship. A.L.H. is funded by Cancer Research UK, the Oxford Cancer Imaging Centre, the Breast Cancer Research Foundation, and the Oxford NIHR Biomedical Research Centre.

Author information

Authors and Affiliations

  1. CRUK Hypoxia and Angiogenesis Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK

    Karim Bensaad

  2. CRUK Growth Factor Group, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK

    Adrian L. Harris

Authors
  1. Karim Bensaad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adrian L. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karim Bensaad .

Editor information

Editors and Affiliations

  1. Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

    Constantinos Koumenis

  2. Cancer Research, Gray Institute for Radiation Oncology, Oxford, United Kingdom

    Ester Hammond

  3. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA

    Amato Giaccia

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this paper

Cite this paper

Bensaad, K., Harris, A.L. (2014). Hypoxia and Metabolism in Cancer. In: Koumenis, C., Hammond, E., Giaccia, A. (eds) Tumor Microenvironment and Cellular Stress. Advances in Experimental Medicine and Biology, vol 772. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5915-6_1

Download citation

Publish with us

Policies and ethics

Search

Navigation