{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:48:02Z","timestamp":1787064482518,"version":"build-2736575974"},"reference-count":191,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T00:00:00Z","timestamp":1635292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>PFKFB3 is a bifunctional enzyme that modulates and maintains the intracellular concentrations of fructose-2,6-bisphosphate (F2,6-P2), essentially controlling the rate of glycolysis. PFKFB3 is a known activator of glycolytic rewiring in neoplastic cells, including central nervous system (CNS) neoplastic cells. The pathologic regulation of PFKFB3 is invoked via various microenvironmental stimuli and oncogenic signals. Hypoxia is a primary inducer of PFKFB3 transcription via HIF-1alpha. In addition, translational modifications of PFKFB3 are driven by various intracellular signaling pathways that allow PFKFB3 to respond to varying stimuli. PFKFB3 synthesizes F2,6P2 through the phosphorylation of F6P with a donated PO4 group from ATP and has the highest kinase activity of all PFKFB isoenzymes. The intracellular concentration of F2,6P2 in cancers is maintained primarily by PFKFB3 allowing cancer cells to evade glycolytic suppression. PFKFB3 is a primary enzyme responsible for glycolytic tumor metabolic reprogramming. PFKFB3 protein levels are significantly higher in high-grade glioma than in non-pathologic brain tissue or lower grade gliomas, but without relative upregulation of transcript levels. High PFKFB3 expression is linked to poor survival in brain tumors. Solitary or concomitant PFKFB3 inhibition has additionally shown great potential in restoring chemosensitivity and radiosensitivity in treatment-resistant brain tumors. An improved understanding of canonical and non-canonical functions of PFKFB3 could allow for the development of effective combinatorial targeted therapies for brain tumors.<\/jats:p>","DOI":"10.3390\/cells10112913","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T22:00:23Z","timestamp":1635372023000},"page":"2913","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0694-5526","authenticated-orcid":false,"given":"Reinier","family":"Alvarez","sequence":"first","affiliation":[{"name":"Department of Neurological Surgery, University of Colorado School of Medicine, Aurora, CO 80045, USA"},{"name":"Neurosurgery Unit for Pituitary and Inheritable Disorders, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debjani","family":"Mandal","sequence":"additional","affiliation":[{"name":"Neurosurgery Unit for Pituitary and Inheritable Disorders, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant","family":"Chittiboina","sequence":"additional","affiliation":[{"name":"Neurosurgery Unit for Pituitary and Inheritable Disorders, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20824, USA"},{"name":"Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Reid, M.A., Sanderson, S.M., and Locasale, J.W. (2020). Cancer Metabolism, Elsevier Inc.. [6th ed.].","DOI":"10.1016\/B978-0-323-47674-4.00009-8"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.tibs.2018.01.006","article-title":"Metabolic Kinases Moonlighting as Protein Kinases","volume":"43","author":"Lu","year":"2018","journal-title":"Trends Biochem. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3751","DOI":"10.1038\/onc.2014.320","article-title":"How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions?","volume":"34","author":"Lincet","year":"2015","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1146\/annurev-pathol-012513-104720","article-title":"Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology","volume":"9","author":"Semenza","year":"2014","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.ccell.2014.10.006","article-title":"Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia","volume":"26","author":"Jain","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/cdd.2008.21","article-title":"The role of hypoxia-inducible factors in tumorigenesis","volume":"15","author":"Rankin","year":"2008","journal-title":"Cell Death Differ."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/nrc.2016.84","article-title":"Oxygen availability and metabolic adaptations","volume":"16","author":"Nakazawa","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6183","DOI":"10.1074\/jbc.M110978200","article-title":"Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase-3 (PFKFB3) gene: Its possible role in the warburg effect","volume":"277","author":"Minchenko","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1158\/0008-5472.999.65.3","article-title":"Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1\u03b1, causing glycolysis shutdown and cell death","volume":"65","author":"Blum","year":"2005","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.2174\/138955709788922610","article-title":"HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms","volume":"9","author":"Ralph","year":"2009","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ch\u00e9deville, A.L., Lourdusamy, A., Monteiro, A.R., Hill, R., and Madureira, P.A. (2020). Investigating glioblastoma response to hypoxia. Biomedicines, 8.","DOI":"10.3390\/biomedicines8090310"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"53562","DOI":"10.1074\/jbc.M406096200","article-title":"6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia","volume":"279","author":"Obach","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.gde.2009.10.009","article-title":"HIF-1: Upstream and downstream of cancer metabolism","volume":"20","author":"Semenza","year":"2010","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kucharzewska, P., Christianson, H.C., and Belting, M. (2015). Global profiling of metabolic adaptation to hypoxic stress in human glioblastoma cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116740"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.radonc.2009.06.025","article-title":"Pyruvate into lactate and back: From the Warburg effect to symbiotic energy fuel exchange in cancer cells","volume":"92","author":"Feron","year":"2009","journal-title":"Radiother. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1038\/ncb3410","article-title":"Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation","volume":"18","author":"Pan","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s10863-007-9080-3","article-title":"Hypoxia, glucose metabolism and the Warburg\u2019s effect","volume":"39","author":"Bartrons","year":"2007","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1038\/onc.2016.411","article-title":"Cancer heterogeneity is not compatible with one unique cancer cell metabolic map","volume":"36","author":"Strickaert","year":"2017","journal-title":"Oncogene"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.cell.2015.12.034","article-title":"Metabolic Heterogeneity in Human Lung Tumors","volume":"164","author":"Hensley","year":"2016","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0307-4412(74)90017-X","article-title":"Regulation in Metabolism. Strategy of drug design: A molecular guide to biological activity. Essentials of Organic Nomenclature\u2014A Programmed course","volume":"Volume 2","author":"Newsholme","year":"1974","journal-title":"Biochemical Education"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj2060001","article-title":"Fructose 2,6-bisphosphate 2 years after its discovery","volume":"206","author":"Hers","year":"1982","journal-title":"Biochem. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1146\/annurev.bi.64.070195.004055","article-title":"6-Phosphofructo-2-kinase\/fructose-2,6-bisphosphatase: A metabolic signaling enzyme","volume":"64","author":"Pilkis","year":"1995","journal-title":"Annu. Rev. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s11060-007-9471-7","article-title":"6-Phosphofructo-2-kinase\/fructose-2,6-bisphosphatase (PFKFB3) is up-regulated in high-grade astrocytomas","volume":"86","author":"Kessler","year":"2008","journal-title":"J. Neurooncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.cell.2013.06.037","article-title":"Role of PFKFB3-driven glycolysis in vessel sprouting","volume":"154","author":"Georgiadou","year":"2013","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"24223","DOI":"10.1074\/jbc.M109.016816","article-title":"Nuclear targeting of 6-phosphofructo-2-kinase (PFKFB3) increases proliferation via cyclin-dependent kinases","volume":"284","author":"Yalcin","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-06287-x","article-title":"Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination","volume":"9","author":"Gustafsson","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/biof.5520100101","article-title":"Fructose-2,6-bisphosphate and control of carbohydrate metabolism in eukaryotes","volume":"10","author":"Okar","year":"1999","journal-title":"BioFactors"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/S0169-328X(01)00014-6","article-title":"Splice isoforms of ubiquitous 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase in human brain","volume":"87","author":"Kessler","year":"2001","journal-title":"Mol. Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.bbrc.2005.02.193","article-title":"Targeted disruption of inducible 6-phosphofructo-2-kinase results in embryonic lethality","volume":"331","author":"Chesney","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1097\/00075197-200109000-00012","article-title":"6-Phosphofructo-2-kinase\/fructose-2,6-bisphosphatase: Suiting structure to need, in a family of tissue-specific enzymes","volume":"4","author":"Noto","year":"2001","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/S0968-0004(00)01699-6","article-title":"PFK-2\/FBPase-2: Maker and breaker of the essential biofactor fructose-2,6-bisphosphate","volume":"26","author":"Okar","year":"2001","journal-title":"Trends Biochem. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1093\/oxfordjournals.jbchem.a021719","article-title":"Characterization of a human placental fructose-6-phosphate, 2-kinase\/fructose-2,6-bisphosphatase","volume":"122","author":"Sakakibara","year":"1997","journal-title":"J. Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1074\/mcp.M113.035600","article-title":"Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics","volume":"13","author":"Fagerberg","year":"2014","journal-title":"Mol. Cell. Proteom."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1159\/000015181","article-title":"Molecular cloning, expression, and chromosomal localization of a ubiquitously expressed human 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase gene (PFKFB3)","volume":"83","author":"Manzano","year":"1998","journal-title":"Cytogenet. Cell Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1073\/pnas.96.6.3047","article-title":"An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: Role in tumor cell glycolysis and the Warburg effect","volume":"96","author":"Chesney","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"24324","DOI":"10.1038\/srep24324","article-title":"PFKFB3 Control of Cancer Growth by Responding to Circadian Clock Outputs","volume":"6","author":"Chen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1177\/1947601911423029","article-title":"Role of Sp Transcription Factors in the Regulation of Cancer Cell Metabolism","volume":"2","author":"Archer","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.1096\/fj.08-106492","article-title":"AP-2\u03b1 and AP-2\u03b3 regulate tumor progression via specific genetic programs","volume":"22","author":"Orso","year":"2008","journal-title":"FASEB J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1093\/jb\/mvh137","article-title":"Identification and characterization of the hypoxia-responsive element of the human placental 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase gene","volume":"136","author":"Fukasawa","year":"2004","journal-title":"J. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9440","DOI":"10.1074\/jbc.M113.529990","article-title":"Estradiol stimulates glucose metabolism via 6-phosphofructo-2-kinase (PFKFB3)","volume":"289","author":"Clem","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1042\/BJ20111418","article-title":"Progestins activate 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase 3 (PFKFB3) in breast cancer cells","volume":"442","author":"Novellasdemunt","year":"2012","journal-title":"Biochem. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1161\/ATVBAHA.114.304277","article-title":"Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3","volume":"35","author":"Doddaballapur","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"10530","DOI":"10.1074\/jbc.RA119.007784","article-title":"Increased 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase-3 activity in response to EGFR signaling contributes to non-small cell lung cancer cell survival","volume":"294","author":"Lypova","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_44","first-page":"1509","article-title":"An E2F-dependent late-serum-response promoter in a gene that controls glycolysis","volume":"11","author":"Darville","year":"1995","journal-title":"Oncogene"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1093\/nar\/gkx1155","article-title":"NRF2 regulates endothelial glycolysis and proliferation with MIR-93 and mediates the effects of oxidized phospholipids on endothelial activation","volume":"46","author":"Kuosmanen","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.2337\/diabetes.54.12.3349","article-title":"Expression of inducible 6-phosphofructo-2-kinase\/fructose-2,6- bisphosphatase\/PFKFB3 isoforms in adipocytes and their potential role in glycolytic regulation","volume":"54","author":"Atsumi","year":"2005","journal-title":"Diabetes"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"789","DOI":"10.18388\/abp.2006_3308","article-title":"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","volume":"53","author":"Bobarykina","year":"2006","journal-title":"Acta Biochim. Pol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"30778","DOI":"10.1074\/jbc.M205213200","article-title":"The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase","volume":"277","author":"Marsin","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7225","DOI":"10.1038\/sj.onc.1209709","article-title":"Ras transformation requires metabolic control by 6-phosphofructo-2-kinase","volume":"25","author":"Telang","year":"2006","journal-title":"Oncogene"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/0003-9861(91)90084-V","article-title":"Regulation of 6-phosphofructo-1-kinase activity in ras-transformed rat-1 fibroblasts","volume":"286","author":"Kole","year":"1991","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1038\/s41388-018-0157-8","article-title":"Targeting PFKFB3 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitor","volume":"37","author":"Zhu","year":"2018","journal-title":"Oncogene"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1042\/bj20020622","article-title":"An E2F-binding site mediates the activation of the proliferative isoform of 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase by phosphatidylinositol 3-kinase","volume":"368","author":"Lam","year":"2002","journal-title":"Biochem. J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-020-01639-2","article-title":"Hypoxia, metabolism, and the circadian clock: New links to overcome radiation resistance in high-grade gliomas","volume":"39","author":"Shen","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s10549-016-3968-8","article-title":"Inhibition of 6-phosphofructo-2-kinase (PFKFB3) suppresses glucose metabolism and the growth of HER2+ breast cancer","volume":"160","author":"Clem","year":"2016","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0167-4889(02)00169-6","article-title":"Insulin induces PFKFB3 gene expression in HT29 human colon adenocarcinoma cells","volume":"1589","author":"Riera","year":"2002","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1272\/jnms.77.97","article-title":"Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase-3","volume":"77","author":"Ando","year":"2010","journal-title":"J. Nippon Med. Sch."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"19247","DOI":"10.1074\/jbc.M110.190298","article-title":"Cooperation of adenosine with macrophage toll-4 receptor agonists leads to increased glycolytic flux through the enhanced expression of PFKFB3 gene","volume":"286","author":"Monsalve","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.cellsig.2017.02.019","article-title":"Role of Akt\/PKB and PFKFB isoenzymes in the control of glycolysis, cell proliferation and protein synthesis in mitogen-stimulated thymocytes","volume":"34","author":"Houddane","year":"2017","journal-title":"Cell. Signal."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s11010-018-3325-9","article-title":"PI3K\u2013Akt signaling controls PFKFB3 expression during human T-lymphocyte activation","volume":"448","author":"Fontova","year":"2018","journal-title":"Mol. Cell. Biochem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3437","DOI":"10.1111\/febs.14201","article-title":"TGF-\u03b21 targets Smad, p38 MAPK, and PI3K\/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells","volume":"284","author":"Fontova","year":"2017","journal-title":"FEBS J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1042\/BJ20121886","article-title":"PFKFB3 activation in cancer cells by the p38\/MK2 pathway in response to stress stimuli","volume":"452","author":"Novellasdemunt","year":"2013","journal-title":"Biochem. J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s10456-020-09760-8","article-title":"YAP promotes ocular neovascularization by modifying PFKFB3-driven endothelial glycolysis","volume":"24","author":"Feng","year":"2021","journal-title":"Angiogenesis"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Kumar, P., Sharoyko, V.V., Sp\u00e9gel, P., Gullberg, U., Mulder, H., Olsson, I., and Ajore, R. (2013). The Transcriptional Co-Repressor Myeloid Translocation Gene 16 Inhibits Glycolysis and Stimulates Mitochondrial Respiration. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068502"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"38067","DOI":"10.1038\/srep38067","article-title":"P53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway","volume":"6","author":"Franklin","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"41600","DOI":"10.1074\/jbc.M111.240812","article-title":"Inhibition of glycolytic enzymes mediated by pharmacologically activated p53: Targeting Warburg effect to fight cancer","volume":"286","author":"Grinkevich","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.bbrc.2015.06.068","article-title":"Overexpression of miR-206 suppresses glycolysis, proliferation and migration in breast cancer cells via PFKFB3 targeting","volume":"463","author":"Ge","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.3892\/or.2015.3797","article-title":"MiR-26b inhibits proliferation, migration, invasion and apoptosis induction via the downregulation of 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase-3 driven glycolysis in osteosarcoma cells","volume":"33","author":"Du","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_68","first-page":"1","article-title":"Modulation of LXR signaling altered the dynamic activity of human colon adenocarcinoma cancer stem cells in vitro","volume":"21","author":"Khalili","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1271\/bbb.62.2039","article-title":"A common phosphorylation site for cyclic AMP-dependent protein kinase and protein kinase C in human placental 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase","volume":"62","author":"Okamura","year":"1998","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4235","DOI":"10.1016\/j.celrep.2020.03.005","article-title":"c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3","volume":"30","author":"Ma","year":"2020","journal-title":"Cell Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4524","DOI":"10.1158\/0008-5472.CAN-17-0385","article-title":"Expression of long noncoding RNA YIYA promotes glycolysis in breast cancer","volume":"78","author":"Xing","year":"2018","journal-title":"Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1038\/ncb3231","article-title":"AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest","volume":"17","author":"Maestre","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1101\/gad.287235.116","article-title":"IKK\u03b2 promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3","volume":"30","author":"Reid","year":"2016","journal-title":"Genes Dev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.jmb.2013.11.021","article-title":"PFKFB3 regulates oxidative stress homeostasis via its S-glutathionylation in cancer","volume":"426","author":"Seo","year":"2014","journal-title":"J. Mol. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3480","DOI":"10.1038\/ncomms4480","article-title":"Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway","volume":"5","author":"Yamamoto","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jmb.2007.03.038","article-title":"A Direct Substrate-Substrate Interaction Found in the Kinase Domain of the Bifunctional Enzyme, 6-Phosphofructo-2-kinase\/Fructose-2,6-bisphosphatase","volume":"370","author":"Kim","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"36020","DOI":"10.1074\/jbc.M113.510289","article-title":"Increased concentrations of fructose 2,6-bisphosphate contribute to the Warburg effect in phosphatase and tensin homolog (PTEN)-deficient cells","volume":"288","author":"Hagen","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5278","DOI":"10.1073\/pnas.1102247108","article-title":"Two ubiquitin ligases, APC\/C-Cdh1 and SKP1-CUL1-F (SCF)-\u03b2-TrCP, sequentially regulate glycolysis during the cell cycle","volume":"108","author":"Tudzarova","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/ncb1881","article-title":"The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC\/C-Cdh1","volume":"11","author":"Almeida","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1038\/s41467-020-15112-3","article-title":"Long noncoding RNA AGPG regulates PFKFB3-mediated tumor glycolytic reprogramming","volume":"11","author":"Liu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_81","first-page":"5881","article-title":"High expression of inducible 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers","volume":"62","author":"Atsumi","year":"2002","journal-title":"Cancer Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"215","DOI":"10.3892\/ijo.2015.3225","article-title":"Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer","volume":"48","author":"Han","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"5784","DOI":"10.1158\/1078-0432.CCR-05-0149","article-title":"Phosphorylation of the 6-phosphofructo-2-kinase\/fructose 2,6-bisphosphatase\/PFKFB3 family of glycolytic regulators in human cancer","volume":"11","author":"Bando","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.bbrc.2017.01.178","article-title":"6-phosphofructo-2-kinase\/fructose 2,6-bisphosphatase-3 is required for transforming growth factor \u03b21-enhanced invasion of Panc1 cells in vitro","volume":"484","author":"Yalcin","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/leu.2011.225","article-title":"The JAK2V617F oncogene requires expression of inducible phosphofructokinase\/fructose-bisphosphatase 3 for cell growth and increased metabolic activity","volume":"26","author":"Reddy","year":"2012","journal-title":"Leukemia"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"29753","DOI":"10.18632\/oncotarget.4995","article-title":"The expression pattern of PFKFB3 enzyme distinguishes between induced-pluripotent stem cells and cancer stem cells","volume":"6","author":"Jain","year":"2015","journal-title":"Oncotarget"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"382","DOI":"10.4161\/auto.27345","article-title":"The glycolytic enzyme PFKFB3\/phosphofructokinase regulates autophagy","volume":"10","author":"Yang","year":"2014","journal-title":"Autophagy"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"80909","DOI":"10.18632\/oncotarget.20757","article-title":"6-Phosphofructo-2-kinase\/fructose-2,6-bisphosphatase isoform 3 spatially mediates autophagy through the AMPK signaling pathway","volume":"8","author":"Yan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"8394","DOI":"10.1016\/S0021-9258(19)68856-3","article-title":"The effect of natural and synthetic D-fructose 2,6-bisphosphate on the regulatory kinetic properties of liver and muscle phosphofructokinases","volume":"256","author":"Uyeda","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"Injuring of Respiration the Origin of Cancer Cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"12486","DOI":"10.1073\/pnas.1402012111","article-title":"Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter","volume":"111","author":"Le","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/nrc1478","article-title":"Why do cancers have high aerobic glycolysis?","volume":"4","author":"Gatenby","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1073\/pnas.78.5.2861","article-title":"Inhibition of fructose-1,6-bisphosphatase by fructose 2,6-biphosphate","volume":"78","author":"Hers","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.celrep.2014.03.057","article-title":"Constant Growth Rate Can Be Supported by Decreasing Energy Flux and Increasing Aerobic Glycolysis","volume":"7","author":"Slavov","year":"2014","journal-title":"Cell Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/0027-5107(92)90235-T","article-title":"Clastogenicity of low pH to various cultured mammalian cells","volume":"268","author":"Morita","year":"1992","journal-title":"Mutat. Res. Fundam. Mol. Mech. Mutagen."},{"key":"ref_96","first-page":"165","article-title":"The pro-tumorigenic effects of metabolic alterations in glioblastoma including brain tumor initiating cells","volume":"1869","author":"Libby","year":"2018","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"7245","DOI":"10.7150\/thno.44427","article-title":"Dual inhibition of PFKFB3 and VEGF normalizes tumor vasculature, reduces lactate production, and improves chemotherapy in glioblastoma: Insights from protein expression profiling and MRI","volume":"10","author":"Zhang","year":"2020","journal-title":"Theranostics"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1158\/1535-7163.MCT-15-0247","article-title":"Sensitization of glioblastoma cells to irradiation by modulating the glucose metabolism","volume":"14","author":"Shen","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Kelley, K., Knisely, J., Symons, M., and Ruggieri, R. (2016). Radioresistance of brain tumors. Cancers, 8.","DOI":"10.3390\/cancers8040042"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.molmed.2017.01.008","article-title":"Targeting PFKFB3 in the Endothelium for Cancer Therapy","volume":"23","author":"Yang","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.neo.2020.12.009","article-title":"Glycolysis-induced drug resistance in tumors\u2014A response to danger signals?","volume":"23","author":"Marcucci","year":"2021","journal-title":"Neoplasia"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molmet.2018.11.013","article-title":"6-Phosphofructo-2-kinase\/fructose-2,6-biphosphatase 3 and 4: A pair of valves for fine-tuning of glucose metabolism in human cancer","volume":"20","author":"Yi","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.gene.2012.08.038","article-title":"The influence of reactive oxygen species on cell cycle progression in mammalian cells","volume":"511","author":"Verbon","year":"2012","journal-title":"Gene"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"5662","DOI":"10.1038\/onc.2015.23","article-title":"Identification of 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase as a novel autophagy regulator by high content shRNA screening","volume":"34","author":"Strohecker","year":"2015","journal-title":"Oncogene"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.tibs.2014.06.005","article-title":"The pentose phosphate pathway and cancer","volume":"39","author":"Patra","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1161\/ATVBAHA.113.303041","article-title":"Endothelial PFKFB3 plays a critical role in angiogenesis","volume":"34","author":"Xu","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.ccell.2016.10.006","article-title":"Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy","volume":"30","author":"Cantelmo","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cmet.2013.11.008","article-title":"Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis","volume":"19","author":"Schoors","year":"2014","journal-title":"Cell Metab."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.cytogfr.2014.07.009","article-title":"The multifaceted activity of VEGF in angiogenesis\u2014Implications for therapy responses","volume":"25","author":"Moens","year":"2014","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nrd3455","article-title":"Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases","volume":"10","author":"Carmeliet","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.cell.2009.01.020","article-title":"Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization","volume":"136","author":"Mazzone","year":"2009","journal-title":"Cell"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"19059","DOI":"10.1073\/pnas.1318022110","article-title":"Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation","volume":"110","author":"Batchelor","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41467-018-02950-5","article-title":"Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis","volume":"9","author":"Li","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/s41419-018-0435-y","article-title":"PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT article","volume":"9","author":"Shi","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"e1337","DOI":"10.1038\/cddis.2014.292","article-title":"6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27","volume":"5","author":"Yalcin","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.dnarep.2018.07.008","article-title":"Multiple functions of p27 in cell cycle, apoptosis, epigenetic modification and transcriptional regulation for the control of cell growth: A double-edged sword protein","volume":"69","author":"Abbastabar","year":"2018","journal-title":"DNA Repair"},{"key":"ref_117","first-page":"1","article-title":"The role of CDC25C in cell cycle regulation and clinical cancer therapy: A systematic review","volume":"20","author":"Liu","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/sj.onc.1202016","article-title":"Cyclin D3: Requirement for G1\/S transition and high abundance in quiescent tissues suggest a dual role in proliferation and differentiation","volume":"17","author":"Bartkova","year":"1998","journal-title":"Oncogene"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1038\/s41388-017-0072-4","article-title":"Non-canonical roles of PFKFB3 in regulation of cell cycle through binding to CDK4","volume":"37","author":"Jia","year":"2018","journal-title":"Oncogene"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1093\/neuonc\/nou058","article-title":"Role of AKT signaling in DNA repair and clinical response to cancer therapy","volume":"16","author":"Liu","year":"2014","journal-title":"Neuro Oncol."},{"key":"ref_121","first-page":"3223","article-title":"Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs","volume":"30","author":"Kirschner","year":"2010","journal-title":"Anticancer Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"4861","DOI":"10.1158\/0008-5472.CAN-04-2633","article-title":"Akt activation suppresses Chk2-mediated, methylating agent-induced G 2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence","volume":"65","author":"Hirose","year":"2005","journal-title":"Cancer Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1101\/gad.1863810","article-title":"Essential role of Tip60-dependent recruitment of ribonucleotide reductase at DNA damage sites in DNA repair during G1 phase","volume":"24","author":"Niida","year":"2010","journal-title":"Genes Dev."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"IV1","DOI":"10.1093\/neuonc\/noaa200","article-title":"CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2013\u20132017","volume":"22","author":"Ostrom","year":"2020","journal-title":"Neuro Oncol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1093\/neuonc\/nou087","article-title":"The epidemiology of glioma in adults: A state of the science review","volume":"16","author":"Ostrom","year":"2014","journal-title":"Neuro Oncol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.ejpb.2016.09.018","article-title":"Inhibition of carbonic anhydrase IX in glioblastoma multiforme","volume":"109","author":"Amiri","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1111\/j.1365-2990.2009.01027.x","article-title":"The PFKFB3 splice variant UBI2K4 is downregulated in high-grade astrocytomas and impedes the growth of U87 glioblastoma cells","volume":"35","author":"Zscharnack","year":"2009","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1093\/jnen\/nlz067","article-title":"Prognostic Value of PFKFB3 to PFKFB4 mRNA Ratio in Patients With Primary Glioblastoma (IDH-Wildtype)","volume":"78","author":"Kessler","year":"2019","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1002\/gcc.20914","article-title":"LOH on 10p14-p15 targets the PFKFB3 gene locus in human glioblastomas","volume":"50","author":"Fleischer","year":"2011","journal-title":"Genes. Chromosomes Cancer"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12935-019-1005-9","article-title":"The influence of PFK-II overexpression on neuroblastoma patients\u2019 survival may be dependent on the particular isoenzyme expressed, PFKFB3 or PFKFB4","volume":"19","author":"Trojan","year":"2019","journal-title":"Cancer Cell Int."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"304ra143","DOI":"10.1126\/scitranslmed.aac6762","article-title":"The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma","volume":"7","author":"Venere","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1158\/1541-7786.MCR-18-1361","article-title":"Hyperphosphorylation of CDH1 in glioblastoma cancer stem cells attenuates APC\/CCDH1 activity and pharmacologic inhibition of APC\/CCDH1\/CDC20 compromises viability","volume":"17","author":"De","year":"2019","journal-title":"Mol. Cancer Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1093\/jnen\/59.6.539","article-title":"Loss of heterozygosity on chromosome 19 in secondary glioblastomas","volume":"59","author":"Nakamura","year":"2000","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_134","first-page":"2243","article-title":"Chromosome 10 deletion mapping in human gliomas: A common deletion region in 10q25","volume":"10","author":"Rasheed","year":"1995","journal-title":"Oncogene"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.isci.2019.09.040","article-title":"Phosphofructokinases Axis Controls Glucose-Dependent mTORC1 Activation Driven by E2F1","volume":"20","author":"Almacellas","year":"2019","journal-title":"iScience"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3233\/CBM-161628","article-title":"E2F transcription factors associated with up-regulated genes in glioblastoma","volume":"18","author":"Donaires","year":"2017","journal-title":"Cancer Biomark."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1093\/neuonc\/noy150","article-title":"Inhibition of mTORC1 in pediatric low-grade glioma depletes glutathione and therapeutically synergizes with carboplatin","volume":"21","author":"Poore","year":"2019","journal-title":"Neuro Oncol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1093\/neuonc\/noz230","article-title":"Synergistic activity of mTORC1\/2 kinase and MEK inhibitors suppresses pediatric low-grade glioma tumorigenicity and vascularity","volume":"22","author":"Arnold","year":"2020","journal-title":"Neuro Oncol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"S475","DOI":"10.4103\/2152-7806.185781","article-title":"MTORC1 signaling in primary central nervous system lymphoma","volume":"7","author":"Nitta","year":"2016","journal-title":"Surg. Neurol. Int."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ccell.2017.01.014","article-title":"A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma","volume":"31","author":"Fan","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_141","first-page":"2742","article-title":"Analysis of the phosphatidylinositol 3\u2032-kinase signaling pathway in glioblastoma patients in vivo","volume":"63","author":"Choe","year":"2003","journal-title":"Cancer Res."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1056\/NEJMoa1001671","article-title":"Everolimus for Subependymal Giant-Cell Astrocytomas in Tuberous Sclerosis","volume":"363","author":"Krueger","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1093\/jnen\/64.4.341","article-title":"Lhermitte-Duclos disease: A report of 31 cases with immunohistochemical analysis of the PTEN\/AKT\/mTOR pathway","volume":"64","author":"Abel","year":"2005","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1002\/iub.2232","article-title":"Upregulation of 6-phosphofructo-2-kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex","volume":"72","author":"Wang","year":"2020","journal-title":"IUBMB Life"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1007\/s004390000390","article-title":"Molecular analysis of the TSC1 and TSC2 tumour suppressor genes in sporadic glial and glioneuronal tumours","volume":"107","author":"Parry","year":"2000","journal-title":"Hum. Genet."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/1476-4598-12-127","article-title":"R-RAS2 overexpression in tumors of the human central nervous system","volume":"12","author":"Fresno","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ccr.2006.11.023","article-title":"High TGF\u03b2-Smad Activity Confers Poor Prognosis in Glioma Patients and Promotes Cell Proliferation Depending on the Methylation of the PDGF-B Gene","volume":"11","author":"Bruna","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"983","DOI":"10.21873\/anticanres.14852","article-title":"Epidermal growth factor receptor and its oncogenic egfrviii variant in benign and malignant brain tumors","volume":"41","author":"Kielbus","year":"2021","journal-title":"Anticancer Res."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.radonc.2020.09.036","article-title":"Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma","volume":"154","author":"Biau","year":"2021","journal-title":"Radiother. Oncol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1093\/neuonc\/now113","article-title":"EGFRvIII mutations can emerge as late and heterogenous events in glioblastoma development and promote angiogenesis through Src activation","volume":"18","author":"Eskilsson","year":"2016","journal-title":"Neuro Oncol."},{"key":"ref_151","first-page":"1883","article-title":"Momelotinib sensitizes glioblastoma cells to temozolomide by enhancement of autophagy via JAK2\/STAT3 inhibition","volume":"41","author":"Liu","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/s41419-020-03241-y","article-title":"Autocrine IL-6\/STAT3 signaling aids development of acquired drug resistance in Group 3 medulloblastoma","volume":"11","author":"Sreenivasan","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"112612","DOI":"10.1016\/j.ejmech.2020.112612","article-title":"PFKFB3 inhibitors as potential anticancer agents: Mechanisms of action, current developments, and structure-activity relationships","volume":"203","author":"Wang","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1158\/1535-7163.MCT-07-0482","article-title":"Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth","volume":"7","author":"Clem","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-016-0481-1","article-title":"Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma","volume":"36","author":"Li","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Zhu, W., Ye, L., Zhang, J., Yu, P., Wang, H., Ye, Z., and Tian, J. (2016). PFK15, a small molecule inhibitor of PFKFB3, induces cell cycle arrest, apoptosis and inhibits invasion in gastric cancer. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163768"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/j.celrep.2016.04.028","article-title":"Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy","volume":"15","author":"Pisarsky","year":"2016","journal-title":"Cell Rep."},{"key":"ref_158","first-page":"5889","article-title":"Inhibition of growth of bladder cancer cells by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one in combination with other compounds affecting glucose metabolism","volume":"35","author":"Lea","year":"2015","journal-title":"Anticancer Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1158\/1535-7163.MCT-13-0097","article-title":"Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer","volume":"12","author":"Clem","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1002\/1873-3468.13878","article-title":"Small molecule 3PO inhibits glycolysis but does not bind to 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase-3 (PFKFB3)","volume":"594","author":"Perrotta","year":"2020","journal-title":"FEBS Lett."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/ijc.31868","article-title":"Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers","volume":"144","author":"Mondal","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s41419-019-1916-3","article-title":"PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses","volume":"10","author":"Thirusangu","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1038\/s41388-020-01621-4","article-title":"Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer","volume":"40","author":"Xiao","year":"2021","journal-title":"Oncogene"},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"De Oliveira, T., Goldhardt, T., Edelmann, M., Rogge, T., Rauch, K., Kyuchukov, N.D., Menck, K., Bleckman, A., Kalucka, J., and Khan, S. (2021). Effects of the novel pfkfb3 inhibitor kan0438757 on colorectal cancer cells and its systemic toxicity evaluation in vivo. Cancers, 13.","DOI":"10.3390\/cancers13051011"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1002\/ijc.31022","article-title":"By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma","volume":"141","author":"Li","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"Yan, S., Zhou, N., Zhang, D., Zhang, K., Zheng, W., Bao, Y., and Yang, W. (2019). PFKFB3 inhibition attenuates oxaliplatin-induced autophagy and enhances its cytotoxicity in colon cancer cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215415"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1158\/1541-7786.MCR-06-0086","article-title":"Effect of an epidermal growth factor receptor inhibitor in mouse models of lung cancer","volume":"4","author":"Yan","year":"2006","journal-title":"Mol. Cancer Res."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1007\/s10014-013-0174-9","article-title":"The mechanism of chemoresistance against tyrosine kinase inhibitors in malignant glioma","volume":"31","author":"Nakada","year":"2014","journal-title":"Brain Tumor Pathol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.ijrobp.2003.09.092","article-title":"The contribution of epidermal growth factor receptor (EGFR) signaling pathway to radioresistance in human gliomas: A review of preclinical and correlative clinical data","volume":"58","author":"Chakravarti","year":"2004","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"21206","DOI":"10.1074\/jbc.M703042200","article-title":"Inhibition of phosphatidylinositol-3-OH kinase\/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation","volume":"282","author":"Kao","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3389\/fonc.2013.00110","article-title":"The Combination of Novel Targeted Molecular Agents and Radiation in the Treatment of Pediatric Gliomas","volume":"3","author":"Dasgupta","year":"2013","journal-title":"Front. Oncol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ccr.2011.11.023","article-title":"Rapid decrease in delivery of chemotherapy to tumors after anti-vegf therapy: Implications for scheduling of anti-angiogenic drugs","volume":"21","author":"VanderVeldt","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/j.ajpath.2017.01.010","article-title":"Hypoxia-Mediated Mechanisms Associated with Antiangiogenic Treatment Resistance in Glioblastomas","volume":"187","author":"Mahase","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s00401-014-1352-5","article-title":"Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas","volume":"129","author":"Fack","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s10456-017-9573-6","article-title":"Tumor vessel disintegration by maximum tolerable PFKFB3 blockade","volume":"20","author":"Conradi","year":"2017","journal-title":"Angiogenesis"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"105592","DOI":"10.1016\/j.phrs.2021.105592","article-title":"In vitro angiogenesis inhibition with selective compounds targeting the key glycolytic enzyme PFKFB3","volume":"168","author":"Abdali","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"5296","DOI":"10.1158\/0008-5472.CAN-09-0814","article-title":"A \u201cvascular normalization index\u201d as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients","volume":"69","author":"Sorensen","year":"2009","journal-title":"Cancer Res."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1056\/NEJMoa1412082","article-title":"Nivolumab in Previously Untreated Melanoma without BRAF Mutation","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/j.1749-6632.2009.04938.x","article-title":"Targets of protective tumor immunity","volume":"1174","author":"Dranoff","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.ccr.2004.08.031","article-title":"Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis","volume":"6","author":"Yang","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.3389\/fimmu.2018.01004","article-title":"Immune microenvironment in glioblastoma subtypes","volume":"9","author":"Chen","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1146\/annurev.immunol.25.022106.141609","article-title":"Immunosuppressive strategies that are mediated by tumor cells","volume":"25","author":"Rabinovich","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1172\/JCI31422","article-title":"Altered macrophage differentiation and immune dysfunction in tumor development","volume":"117","author":"Sica","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1189\/jlb.5VMR1116-458RRR","article-title":"Myeloid-derived suppressor cells\u2014A new therapeutic target to overcome resistance to cancer immunotherapy","volume":"102","author":"Chesney","year":"2017","journal-title":"J. Leukoc. Biol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1084\/jem.20100587","article-title":"HIF-1\u03b1 regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment","volume":"207","author":"Corzo","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1158\/1078-0432.CCR-11-1591","article-title":"Molecular pathways: Hypoxia response in immune cells fighting or promoting cancer","volume":"18","author":"Melero","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_187","doi-asserted-by":"crossref","unstructured":"Liu, Z., Xu, J., Ma, Q., Zhang, X., Yang, Q., Wang, L., Cao, Y., Xu, Z., Tawfik, A., and Sun, Y. (2020). Glycolysis links reciprocal activation of myeloid cells and endothelial cells in the retinal angiogenic niche. Sci. Transl. Med., 12.","DOI":"10.1126\/scitranslmed.aay1371"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/s41590-019-0433-y","article-title":"Mechanisms of immunotherapy resistance: Lessons from glioblastoma","volume":"20","author":"Jackson","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1158\/2159-8290.CD-19-1355","article-title":"Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner","volume":"10","author":"Bayik","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_190","doi-asserted-by":"crossref","unstructured":"Faubert, B., Solmonson, A., and DeBerardinis, R.J. (2020). Metabolic reprogramming and cancer progression. Science, 368.","DOI":"10.1126\/science.aaw5473"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1089\/ars.2007.1674","article-title":"Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms","volume":"9","author":"Hunt","year":"2007","journal-title":"Antioxid. Redox Signal."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/2913\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:16Z","timestamp":1760167276000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/11\/2913"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,27]]},"references-count":191,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["cells10112913"],"URL":"https:\/\/doi.org\/10.3390\/cells10112913","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,27]]}}}