Abstract
Glycolysis has been one of the major hallmarks of cancer, as cancer cells exhibit a high rate of glucose consumption beyond that required for energy production. Glucose acts as a substrate to generate biomass and regulates cell signaling that is required for the cancer progression. Glucose transporters (GLUTs) have been majorly playing their role in glucose transport across the cell membrane to meet their metabolic demands. Overexpression of GLUTs has been reported in various cancer types. Also, activation of certain oncogenes such as c-myc, ras, and src and several other transcription factors such as hypoxia inducible factor-1α induces the overexpression of GLUTs in cancer cells. GLUT regulation has been studied on the epigenetic level as well to provide fundamental information on its regulation. Targeting and understanding GLUTs function in cancer cells could pave novel path for therapeutic strategies against cancer.
Graphical Abstract
Keywords
- GLUTs
- Glycolysis
- Warburg effect
- Epigenetics
- c-myc
- Mtor
- Cancer
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Abel ED, Kaulbach HC, Tian R, Hopkins JCA, Duffy J, Doetschman T, Minnemann T, Boers M-E, Hadro E, Oberste-Berghaus C, et al. Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. J Clin Invest. 1999;104:1703–14.
Apostolou E, Ferrari F, Walsh RM, Bar-Nur O, Stadtfeld M, Cheloufi S, Stuart HT, Polo JM, Ohsumi TK, Borowsky ML, et al. Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming. Cell Stem Cell. 2013;12:699–712.
Augustin R. The protein family of glucose transport facilitators: it’s not only about glucose after all. IUBMB Life. 2010;62:315–33.
Baldwin SA, Barros LF, Griffiths M. Trafficking of glucose transporters–signals and mechanisms. Biosci Rep. 1995;15:419–26.
Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP, Roth RA. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem. 1999;274:20281–6.
Chai YJ, Yi JW, Oh SW, Kim YA, Yi KH, Kim JH, Lee KE. Upregulation of SLC2 (GLUT) family genes is related to poor survival outcomes in papillary thyroid carcinoma: analysis of data from The Cancer Genome Atlas. Surgery. 2017;161:188–94.
Chen L-Q, Hou B-H, Lalonde S, Takanaga H, Hartung ML, Qu X-Q, Guo W-J, Kim J-G, Underwood W, Chaudhuri B, et al. Sugar transporters for intercellular exchange and nutrition of pathogens. Nature. 2010;468:527–32.
Christensen DR, Calder PC, Houghton FD. GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells. Sci Rep. 2015;5:17500.
Dittmann K, Mayer C, Rodemann HP, Huber SM. EGFR cooperates with glucose transporter SGLT1 to enable chromatin remodeling in response to ionizing radiation. Radiother Oncol. 2013;107:247–51.
Estrada DE, Elliott E, Zinman B, Poon I, Liu Z, Klip A, Daneman D. Regulation of glucose transport and expression of GLUT3 transporters in human circulating mononuclear cells: studies in cells from insulin-dependent diabetic and nondiabetic individuals. Metabolism. 1994;43:591–8.
Evans A, Bates V, Troy H, Hewitt S, Holbeck S, Chung Y-L, Phillips R, Stubbs M, Griffiths J, Airley R. Glut-1 as a therapeutic target: increased chemoresistance and HIF-1-independent link with cell turnover is revealed through COMPARE analysis and metabolomic studies. Cancer Chemother Pharmacol. 2008;61:377–93.
Fass L. Imaging and cancer: a review. Mol Oncol. 2008;2:115–52.
Fei X, Qi M, Wu B, Song Y, Wang Y, Li T. MicroRNA-195-5p suppresses glucose uptake and proliferation of human bladder cancer T24 cells by regulating GLUT3 expression. FEBS Lett. 2012;586:392–7.
Fidler TP, Campbell RA, Funari T, Dunne N, Balderas Angeles E, Middleton EA, Chaudhuri D, Weyrich AS, Abel ED. Deletion of GLUT1 and GLUT3 reveals multiple roles for glucose metabolism in platelet and megakaryocyte function. Cell Rep. 2017;20:881–94.
Flavahan WA, Wu Q, Hitomi M, Rahim N, Kim Y, Sloan AE, Weil RJ, Nakano I, Sarkaria JN, Stringer BW, et al. Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat Neurosci. 2013;16:1373–82.
Fu Y, Maianu L, Melbert BR, Garvey WT. Facilitative glucose transporter gene expression in human lymphocytes, monocytes, and macrophages: a role for GLUT isoforms 1, 3, and 5 in the immune response and foam cell formation. Blood Cells Mol Dis. 2004;32:182–90.
Guillam M-T, Hummler E, Schaerer E, Wu J-Y, Birnbaum MJ, Beermann F, Schmidt A, Deriaz N, Thorens B. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat Genet. 1997;17:327.
Ha T-K, Her N-G, Lee M-G, Ryu B-K, Lee J-H, Han J, Jeong S-I, Kang M-J, Kim N-H, Kim H-J, et al. Caveolin-1 increases aerobic glycolysis in colorectal cancers by stimulating HMGA1-mediated GLUT3 transcription. Cancer Res. 2012;72:4097–109.
Han AL, Veeneman BA, El-Sawy L, Day KC, Day ML, Tomlins SA, Keller ET. Fibulin-3 promotes muscle-invasive bladder cancer. Oncogene. 2017;36:5243–51.
Hong R, Lim S-C. 18F-fluoro-2-deoxyglucose uptake on PET CT and glucose transporter 1 expression in colorectal adenocarcinoma. World J Gastroenterol. 2012;18:168–74.
Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S. Drug resistance in cancer: an overview. Cancer. 2014;6:1769–92.
Huang X-Q, Chen X, Xie X-X, Zhou Q, Li K, Li S, Shen L-F, Su J. Co-expression of CD147 and GLUT-1 indicates radiation resistance and poor prognosis in cervical squamous cell carcinoma. Int J Clin Exp Pathol. 2014;7:1651–66.
Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, Esparza LA, Reya T, Zhan L, Yanxiang Guo J, et al. Glucose feeds the TCA cycle via circulating lactate. Nature. 2017;551:115–8.
Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466:1129–33.
Jacobs SR, Herman CE, MacIver NJ, Wofford JA, Wieman HL, Hammen JJ, Rathmell JC. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol. 2008;180:4476–86.
Kaira K, Endo M, Abe M, Nakagawa K, Ohde Y, Okumura T, Takahashi T, Murakami H, Tsuya A, Nakamura Y, et al. Biologic correlation of 2- [18 F]-Fluoro-2-Deoxy-D-glucose uptake on positron emission tomography in thymic epithelial tumors. J Clin Oncol. 2010;28:3746–53.
Kaira K, Okumura T, Ohde Y, Takahashi T, Murakami H, Oriuchi N, Endo M, Kondo H, Nakajima T, Yamamoto N. Correlation between 18F-FDG uptake on PET and molecular biology in metastatic pulmonary tumors. J Nucl Med. 2011;52:705–11.
Kawauchi K, Araki K, Tobiume K, Tanaka N. p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol. 2008;10:611–8.
Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP. Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature. 2016;531:110–3.
Kim YH, Jeong DC, Pak K, Han M-E, Kim J-Y, Liangwen L, Kim HJ, Kim TW, Kim TH, Hyun DW, et al. SLC2A2 (GLUT2) as a novel prognostic factor for hepatocellular carcinoma. Oncotarget. 2017;8:68381–92.
King BC, Esguerra JLS, Golec E, Eliasson L. CD46 activation regulates miR-150-mediated control of GLUT1 expression and cytokine secretion in human CD4 + T cells. J Immunol. 1950;196:1636–45.
Krzeslak A, Wojcik-Krowiranda K, Forma E, et al. Expression of glut1 and glut3 glucose transporters in endometrial and breast cancers. Pathol Oncol Res. 2012;18:721–8.
Kuang R, Jahangiri A, Mascharak S, Nguyen A, Chandra A, Flanigan PM, Yagnik G, Wagner JR, De Lay M, Carrera D, et al. GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance. JCI Insight. 2017;2:e88815.
Kunkel M, Moergel M, Stockinger M, Jeong J-H, Fritz G, Lehr H-A, Whiteside TL. Overexpression of GLUT-1 is associated with resistance to radiotherapy and adverse prognosis in squamous cell carcinoma of the oral cavity. Oral Oncol. 2007;43:796–803.
Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15:501–13.
Li L, Liang Y, Kang L, Liu Y, Gao S, Chen S, Li Y, You W, Dong Q, Hong T, et al. Transcriptional regulation of the Warburg effect in cancer by SIX1. Cancer Cell. 2018;33:368–385. e7.
Liu M, Gao J, Huang Q, Jin Y, Wei Z. Downregulating microRNA-144 mediates a metabolic shift in lung cancer cells by regulating GLUT1 expression. Oncol Lett. 2016;11:3772–6.
Locasale JW, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 2011;43(9):869–74.
Loenarz C, Schofield CJ. Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases. Trends Biochem Sci. 2011;36:7–18.
Lopez-Serra P, Marcilla M, Villanueva A, RamosFernandez A, Palau A, Leal L, Wahi JE, SetienBaranda F, Szczesna K, Moutinho C, et al. A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect. Nat Commun. 2014;5:3608.
Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (glut) proteins in cancer. J Cell Physiol. 2005;202:654–62.
Makinoshima H, Takita M, Matsumoto S, Yagishita A, Owada S, Esumi H, Tsuchihara K. Epidermal growth factor receptor (EGFR) signaling regulates global metabolic pathways in EGFR-mutated lung adenocarcinoma. J Biol Chem. 2014;289:20813–23.
Maratou E, Dimitriadis G, Kollias A, Boutati E, Lambadiari V, Mitrou P, Raptis SA. Glucose transporter expression on the plasma membrane of resting and activated white blood cells. Eur J Clin Investig. 2007;37:282–90.
Masin M, Vazquez J, Rossi S, Groeneveld S, Samson N, Schwalie PC, Deplancke B, Frawley LE, Gouttenoire J, Moradpour D, et al. GLUT3 is induced during epithelial-mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer. Cancer Metab. 2014;2:11.
Mathupala SP, Ko YH, Pedersen PL. The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies. Biochim Biophys Acta. 1797;2010:1225–30.
Meneses AM, Medina RA, Kato S, Pinto M, Jaque MP, Lizama I, Garcıa Mde los A, Nualart F, Owen GI. Regulation of GLUT3 and glucose uptake by the cAMP signalling pathway in the breast cancer cell line ZR-75. J Cell Physiol. 2008;214:110–6.
Meynet O, Beneteau M, Jacquin MA, Pradelli LA, Cornille A, Carles M, Ricci J-E. Glycolysis inhibition targets Mcl-1 to restore sensitivity of lymphoma cells to ABT-737-induced apoptosis. Leukemia. 2012;26:1145–7.
Micucci C, Orciari S, Catalano A. Hyperglycemia promotes K-Ras-induced lung tumorigenesis through BASCs amplification. PLoS One. 2014;9:e105550.
Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Asp Med. 2013;34:121–38.
Nagarajan A, Dogra SK, Sun L, Gandotra N, Ho T, Cai G, Cline G, Kumar P, Cowles RA, Wajapeyee N. Paraoxonase 2 facilitates pancreatic cancer growth and metastasis by stimulating GLUT1-mediated glucose transport. Mol Cell. 2017;67:685–701. e6.
Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000;275:21797–800.
Plathow C, Weber WA. Tumor cell metabolism imaging. J Nucl Med. 2008;49:43S–63S.
Pradelli LA, Beneteau M, Chauvin C, Jacquin MA, Marchetti S, Munoz-Pinedo C, Auberger P, Pende M, Ricci J-E. Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation. Oncogene. 2010;29:1641–52.
Qu W, Ding S, Cao G, Wang S, Zheng X, Li G. miR-132 mediates a metabolic shift in prostate cancer cells by targeting Glut1. FEBS Open Bio. 2016;6:735–41.
Sasaki H, Shitara M, Yokota K, Hikosaka Y, Moriyama S, Yano M, Fujii Y. Overexpression of GLUT1 correlates with Kras mutations in lung carcinomas. Mol Med Rep. 2012;5:599–602.
Schmidt S, Gawlik V, Holter SM, Augustin R, Scheepers A, Behrens M, Wurst W, Gailus-Durner V, Fuchs H, de Angelis MH, et al. Deletion of glucose transporter GLUT8 in mice increases locomotor activity. Behav Genet. 2008;38:396.
Schmidt S, Hommel A, Gawlik V, Augustin R, Junicke N, Florian S, Richter M, Walther DJ, Montag D, Joost H-G, et al. Essential role of glucose transporter GLUT3 for post-implantation embryonic development. J Endocrinol. 2009;200:23–33.
Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res. 2004;64:2627–33.
Seyer P, Vallois D, Poitry-Yamate C, Schutz F, Metref S, Tarussio D, Maechler P, Staels B, Lanz B, Grueter R, et al. Hepatic glucose sensing is required to preserve b cell glucose competence. J Clin Invest. 2013;123:1662–76.
Shinde SR, Maddika S. PTEN regulates glucose transporter recycling by impairing SNX27 retromer assembly. Cell Rep. 2017;21:1655–66.
Simpson IA, Dwyer D, Malide D, Moley KH, Travis A, Vannucci SJ. The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab. 2008;295:E242–53.
Suh HN, Han HJ. Fibronectin-induced VEGF receptor and calcium channel transactivation stimulate GLUT-1 synthesis and trafficking through PPARc and TC10 in mouse embryonic stem cells. Stem Cell Res. 2013;10:371–86.
Takahashi Y, Akahane T, Yamamoto D, Nakamura H, Sawa H, Nitta K, Ide W, Hashimoto I, Kamada H. Correlation between positron emission tomography findings and glucose transporter 1, 3 and L-type amino acid transporter 1 mRNA expression in primary central nervous system lymphomas. Mol Clin Oncol. 2014;2:525–9.
Tanegashima K, Sato-Miyata Y, Funakoshi M, Nishito Y, Aigaki T, Hara T. Epigenetic regulation of the glucose transporter gene Slc2a1 by β-hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice. Genes Cells. 2017;22:71–83.
Tsukioka M, Matsumoto Y, Noriyuki M, Yoshida C, Nobeyama H, Yoshida H, Yasui T, Sumi T, Honda K-I, Ishiko O. Expression of glucose transporters in epithelial ovarian carcinoma: correlation with clinical characteristics and tumor angiogenesis. Oncol Rep. 2007;18:361–7.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.
Waldhart AN, Dykstra H, Peck AS, Boguslawski EA, Madaj ZB, Wen J, Veldkamp K, Hollowell M, Zheng B, Cantley LC, et al. Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin. Cell Rep. 2017;19:2005–13.
Wang D, Pascual JM, Yang H, Engelstad K, Mao X, Cheng J, Yoo J, Noebels JL, De Vivo CD. A mouse model for Glut-1 haploinsufficiency. Hum Mol Genet. 2006;15:1169–79.
Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8(6):519–30.
Watanabe Y, Suefuji H, Hirose Y, Kaida H, Suzuki G, Uozumi J, Ogo E, Miura M, Takasu K, Miyazaki K, et al. 18F-FDG uptake in primary gastric malignant lymphoma correlates with glucose transporter 1 expression and histologic malignant potential. Int J Hematol. 2013;97:43–9.
Weihua Z, Tsan R, Huang W-C, Wu Q, Chiu C-H, Fidler IJ, Hung M-C. Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell. 2008;13:385–93.
Wellberg EA, Johnson S, Finlay-Schultz J, Lewis AS, Terrell KL, Sartorius CA, Abel ED, Muller WJ, Anderson SM. The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis. Breast Cancer Res. 2016;18:131.
Wieman HL, Wofford JA, Rathmell JC. Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 Kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell. 2007;18:1437–46.
Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, Shen C-H, Wen J, Asara J, McGraw TE, et al. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell. 2013;49:1167–75.
Wuest M, Hamann I, Bouvet V, Glubrecht D, Marshall A, Trayner B, Soueidan O-M, Krys D, Wagner M, Cheeseman C, et al. Molecular imaging of GLUT1 and GLUT5 in breast cancer: a multitracer positron emission tomography imaging study in mice. Mol Pharmacol. 2018;93:79–89.
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S-H, Ito S, Yang C, Wang P, Xiao M-T, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of a-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30.
Yang H, Lin H, Xu H, Zhang L, Cheng L, Wen B, Shou J, Guan K, Xiong Y, Ye D. TETcatalyzed 5-methylcytosine hydroxylation is dynamically regulated by metabolites. Cell Res. 2014;24:1017–20.
Yen T-C, See L-C, Lai C-H, Yah-Huei CW, Ng K-K, Ma S-Y, Lin W-J, Chen J-T, Chen W-J, Lai C-R, et al. 18F-FDG uptake in squamous cell carcinoma of the cervix is correlated with glucose transporter 1 expression. J Nucl Med. 2004;45:22–9.
Young CD, Lewis AS, Rudolph MC, Ruehle MD, Jackman MR, Yun UJ, Ilkun O, Pereira R, Abel ED, Anderson SM. Modulation of glucose transporter 1 (GLUT1) expression levels alters mouse mammary tumor cell growth in vitro and in vivo. PLoS One. 2011;6:e23205.
Yu J, Li J, Zhang S, Xu X, Zheng M, Jiang G, Li F. IGF-1 induces hypoxia-inducible factor 1amediated GLUT3 expression through PI3K/Akt/ mTOR dependent pathways in PC12 cells. Brain Res. 2012;1430:18–24.
Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JKV, Markowitz S, Zhou S, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325:1555–9.
Zha X, Hu Z, Ji S, Jin F, Jiang K, Li C, Zhao P, Tu Z, Chen X, Di L, et al. NFjB up-regulation of glucose transporter 3 is essential for hyperactive mammalian target of rapamycin-induced aerobic glycolysis and tumor growth. Cancer Lett. 2015;359:97–106.
Zhang JZ, Abbud W, Prohaska R, Ismail-Beigi F. Overexpression of stomatin depresses GLUT-1 glucose transporter activity. Am J Phys Cell Physiol. 2001;280:C1277–83.
Zhang C, Liu J, Liang Y, Wu R, Zhao Y, Hong X, Lin M, Yu H, Liu L, Levine AJ, et al. Tumour-associated mutant p53 drives the Warburg effect. Nat Commun. 2013;4:2935.
Zhu A, Lee D, Shim H. Metabolic PET imaging in cancer detection and therapy response. Semin Oncol. 2011;38:55–69.
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Raj, S. et al. (2021). Regulation of Glucose Transporters in Cancer Progression. In: Kesari, K.K., Jha, N.K. (eds) Free Radical Biology and Environmental Toxicity. Molecular and Integrative Toxicology. Springer, Cham. https://doi.org/10.1007/978-3-030-83446-3_9
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