2022
Pyruvate kinase M1 suppresses development and progression of prostate adenocarcinoma
Davidson S, Schmidt D, Heyman J, O'Brien J, Liu A, Israelsen W, Dayton T, Sehgal R, Bronson R, Freinkman E, Mak H, Fanelli G, Malstrom S, Bellinger G, Carracedo A, Pandolfi P, Courtney K, Jha A, DePinho R, Horner J, Thomas C, Cantley L, Loda M, Vander Heiden M. Pyruvate kinase M1 suppresses development and progression of prostate adenocarcinoma. Cancer Research 2022, 82: 2403-2416. PMID: 35584006, PMCID: PMC9256808, DOI: 10.1158/0008-5472.can-21-2352.Peer-Reviewed Original Research
2017
Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer
Biktasova A, Hajek M, Sewell A, Gary C, Bellinger G, Deshpande HA, Bhatia A, Burtness B, Judson B, Mehra S, Yarbrough WG, Issaeva N. Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer. Clinical Cancer Research 2017, 23: 7276-7287. PMID: 28916527, DOI: 10.1158/1078-0432.ccr-17-1438.Peer-Reviewed Original ResearchConceptsClinical trialsHNSCC cellsMatrix metalloproteinasesHuman papillomavirus-associated headNeck squamous cell carcinomaSquamous cell carcinomaAbility of HPVClin Cancer ResTumor cell proliferationNeck cancer cellsWindow trialsCell carcinomaEffective therapyPreclinical modelsHPVHPV oncogenesMouse modelMouse blood vesselsDNA demethylating agentHNSCCXenografted tumorsHPV genesIFN responseTherapyTumor samples
2016
Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion
Juvekar A, Hu H, Yadegarynia S, Lyssiotis C, Ullas S, Lien E, Bellinger G, Son J, Hok R, Seth P, Daly M, Kim B, Scully R, Asara J, Cantley L, Wulf G. Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: e4338-e4347. PMID: 27402769, PMCID: PMC4968752, DOI: 10.1073/pnas.1522223113.Peer-Reviewed Original ResearchMeSH KeywordsAminopyridinesAnimalsAntineoplastic Combined Chemotherapy ProtocolsCell Line, TumorCell ProliferationDNA DamageDNA, NeoplasmFemaleHumansMice, Inbred C57BLMice, Inbred NODMice, KnockoutMice, SCIDMorpholinesNucleosidesPhosphatidylinositol 3-KinasePhosphoinositide-3 Kinase InhibitorsPoly(ADP-ribose) Polymerase InhibitorsTriple Negative Breast NeoplasmsConceptsDNA damagePI3KDNA synthesisNonoxidative pentose phosphate pathwayProtein kinase AktPentose phosphate pathwayKinase AktPI3K inhibitor BKM120DNA repairPI3K inhibitorsPI3K inhibitionPhosphate pathwayCarbon flux studiesCell deathNucleotide synthesisNucleotide triphosphatesMutational backgroundK inhibitionK inhibitorsGenetic aberrationsMouse modelPARP inhibitionInhibitorsBRCA1Triple-negative breast cancerSelective antitumor activity of roscovitine in head and neck cancer
Gary C, Hajek M, Biktasova A, Bellinger G, Yarbrough WG, Issaeva N. Selective antitumor activity of roscovitine in head and neck cancer. Oncotarget 2016, 7: 38598-38611. PMID: 27233076, PMCID: PMC5122414, DOI: 10.18632/oncotarget.9560.Peer-Reviewed Original ResearchConceptsNeck cancerSide effectsGrowth of HPVHPV-negative tissuesHPV-positive headCancer cellsHuman papilloma virusTargeted therapeutic optionsDetectable side effectsNeck cancer cellsNormal cellsDNA damageRoscovitine administrationHPV positivityCyclin-dependent kinase inhibitorTherapeutic optionsUnwanted side effectsPapilloma virusCdk-7Xenografted tumorsP53-dependent cell deathSignificant DNA damageSelective antitumor activitySensitivity of cellsKinase inhibitors
2013
Depletion of a Putatively Druggable Class of Phosphatidylinositol Kinases Inhibits Growth of p53-Null Tumors
Emerling B, Hurov J, Poulogiannis G, Tsukazawa K, Choo-Wing R, Wulf G, Bell E, Shim H, Lamia K, Rameh L, Bellinger G, Sasaki A, Asara J, Yuan X, Bullock A, DeNicola G, Song J, Brown V, Signoretti S, Cantley L. Depletion of a Putatively Druggable Class of Phosphatidylinositol Kinases Inhibits Growth of p53-Null Tumors. Cell 2013, 155: 844-857. PMID: 24209622, PMCID: PMC4070383, DOI: 10.1016/j.cell.2013.09.057.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCell ProliferationCell RespirationCellular SenescenceEmbryo, MammalianGene Knockdown TechniquesGenes, LethalHeterograftsHumansMiceNeoplasm TransplantationPhosphotransferases (Alcohol Group Acceptor)Reactive Oxygen SpeciesSignal TransductionTumor Suppressor Protein p53ConceptsReactive oxygen speciesP53-null tumorsBreast cancer cell linesCancer cell linesBreast cancerType 2Druggable classesAbsence of p53Tumor formationInhibits growthCell linesCancerHomozygous deletionMiceTP53Oxygen speciesP53Enhanced levelsHigh levelsDramatic reductionXenograftsLittermatesTumorsSynthetic lethalityPKM2 Isoform-Specific Deletion Reveals a Differential Requirement for Pyruvate Kinase in Tumor Cells
Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW, Burga LN, Xie J, Jurczak MJ, DePinho RA, Clish CB, Jacks T, Kibbey RG, Wulf GM, Di Vizio D, Mills GB, Cantley LC, Vander Heiden M. PKM2 Isoform-Specific Deletion Reveals a Differential Requirement for Pyruvate Kinase in Tumor Cells. Cell 2013, 155: 397-409. PMID: 24120138, PMCID: PMC3850755, DOI: 10.1016/j.cell.2013.09.025.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceBreast NeoplasmsExonsFemaleGene DeletionGene Knockout TechniquesHeterograftsHumansIsoenzymesMammary Neoplasms, ExperimentalMiceMice, Inbred C57BLModels, MolecularMolecular Sequence DataMutagenesisMutationNeoplasm MetastasisNeoplasm TransplantationPyruvate KinaseRNA SplicingConceptsTumor cellsPKM2 expressionPKM1 expressionTumor formationMammary tumor formationTumor cell proliferationPyruvate kinase M2 isoformPyruvate kinase expressionBreast cancerNull tumorsHuman tumorsTumorsKinase expressionCell proliferationCell populationsPKM2 deletionPKM2 activityCancerPKM2Anabolic metabolismMetabolic requirementsPyruvate kinaseM2 isoformDifferent metabolic requirementsAMPK-Dependent Degradation of TXNIP upon Energy Stress Leads to Enhanced Glucose Uptake via GLUT1
Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, Shen C, Wen J, Asara J, McGraw T, Kahn B, Cantley L. AMPK-Dependent Degradation of TXNIP upon Energy Stress Leads to Enhanced Glucose Uptake via GLUT1. Molecular Cell 2013, 49: 1167-1175. PMID: 23453806, PMCID: PMC3615143, DOI: 10.1016/j.molcel.2013.01.035.Peer-Reviewed Original ResearchConceptsThioredoxin-interacting proteinAMP-dependent protein kinaseGLUT1 messenger RNAMessenger RNAEnergy stressArrestin family proteinGlucose uptakeGlucose transporter GLUT1Negative feedback loopFamily proteinsProtein kinaseProtein productionEnhanced glucose uptakeGLUT1 functionBiochemical mechanismsLong-term adaptationTransporter GLUT1ADP ratioEnergy homeostasisGLUT1Rapid degradationProteinGlucose influxFeedback loopUptakeIdentification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients
Emerling B, Benes C, Poulogiannis G, Bell E, Courtney K, Liu H, Choo-Wing R, Bellinger G, Tsukazawa K, Brown V, Signoretti S, Soltoff S, Cantley L. Identification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 3483-3488. PMID: 23378636, PMCID: PMC3587206, DOI: 10.1073/pnas.1222435110.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDAntigens, NeoplasmBasic Helix-Loop-Helix Transcription FactorsCarcinoma, Renal CellCell Adhesion MoleculesCell HypoxiaCell Line, TumorCell ProliferationGenes, NeoplasmHumansKidney NeoplasmsMiceMice, NudeNeoplasm ProteinsSignal TransductionSrc-Family KinasesSurvival AnalysisXenograft Model Antitumor AssaysConceptsCUB domain-containing protein 1CDCP1 expressionHypoxia-inducible factorTyrosine phosphorylationTarget genesDomain-containing protein 1HIF-2α target genesCancer cell metastasisCancer cell migrationTransmembrane proteinClear cell renal cell carcinoma patientsRenal cell carcinoma patientsShRNA knockdownClear cell renal cell carcinomaCell migrationCell carcinoma patientsCell metastasisCell renal cell carcinomaTumors of patientsRenal cell carcinomaProtein 1Stem cellsPotential therapeutic targetTissue microarray samplesCancer metastasis
2011
Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses
Anastasiou D, Poulogiannis G, Asara J, Boxer M, Jiang J, Shen M, Bellinger G, Sasaki A, Locasale J, Auld D, Thomas C, Vander Heiden M, Cantley L. Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses. Science 2011, 334: 1278-1283. PMID: 22052977, PMCID: PMC3471535, DOI: 10.1126/science.1211485.Peer-Reviewed Original ResearchMeSH KeywordsAcetylcysteineAmino Acid SubstitutionAnimalsAntioxidantsCell LineCell Line, TumorCell SurvivalCysteineDiamideEnzyme ActivatorsGlucoseGlutathioneHumansMiceMice, NudeMutant ProteinsNeoplasm TransplantationNeoplasms, ExperimentalOxidation-ReductionOxidative StressPentose Phosphate PathwayProtein SubunitsPyruvate KinaseReactive Oxygen SpeciesTransplantation, HeterologousConceptsPyruvate kinase M2Lung cancer cellsCancer cellsKinase M2Human lung cancer cellsReactive oxygen species contributesInhibition of PKM2Intracellular reactive oxygen species (ROS) concentrationCancer cell survivalCellular antioxidant responseGlycolytic enzyme pyruvate kinase M2Acute increaseXenograft modelReactive oxygen species concentrationMetabolic changesOxidative stressTumor formationGlucose fluxCell survivalIntracellular concentrationAntioxidant responseInhibitionCellsOxygen species concentrationROS