PI3K-AKT-mTOR

PI3K/Akt/mTORROLESOFAKTINDETERMININGTHEHALLMARKSOFCANCERSelf-sufficiencyingrowthsignalsandinsensitivitytoanti-growthsignals:Aktoverexpressioncanmediateanincreaseincellularresponsetogrowthfactorsintheextra-cellularspaceAktpromotescytoplasmiclocalizationofCKIs,suchasp21andp27,therebyinhibitingtheirfunctionAktstabilizescyclinD1eD3levelsAktfacilitatesMDM2nuclearlocalizationanditsinhibitoryactiononp53InhibitionofapoptosisAktinactivatestheproapopticfactorsBadand(pro)caspase-9AktactivatesIKKenhancingNFκBtranscriptionalactivityonantiapoptoticgenesAktinactivatesForkheadtranscriptionfactors,inhibitingFasLsynthesisROLESOFAKTINDETERMININGTHEHALLMARKSOFCANCER6mTORInhibitors:ExploitingNewTargetsinCancerVascularCellGrowthAktPI3KVEGFRPDGFR-bmTORCancerCellVascularPericyteEndothelialCellTumorAngiogenicFactorsProteinSynthesisBioenergeticsNutrientsGrowthFactorsmTORCellGrowth&Proliferation78mTORMG1G2SCellCycleActivationmTORC1CoordinatesGrowthandNutrientSignalingIncreasedNutrientUptakeSecretionofAngiogenicGrowthFactorsBloodVesselGrowthFactorsNutrientsNutrientAvailability9mTORisaCentralRegulatorofGrowthandMetabolismmTORisanintracellularserine/threoninekinasemTORisacentralregulatorthatsenseschangesin–Availabilityofgrowthfactors1,2–Availabilityofnutrients1,2–Availabilityoffuel/energy3mTORregulationcanaffect–Angiogenesis4–Cellgrowth3–Nutrientuptake,utilization5–Metabolism3CellGrowth&ProliferationProteinSynthesismTORAngiogenesisNutrientsGrowthFactorsNormalCellBioenergetics10mTORIntegratesGrowthFactorSignalingmTORpathway,PI3K-AKT-mTOR,isadownstreamcomponentofseveralgrowthfactorsignalingpathways1mTORactivationturnsonthesynthesisofproteinsinvolvedincellgrowth2mTORisacriticalintegratorofsignalingthatcoordinatescellgrowthcontrol3mTORGrowthSignalingPI3KAktTSC2↑GlucoseTSC1AMPKAminoAcids↑ATP↓Glucose↓ATPCellGrowth&ProliferationProteinSynthesisAngiogenesisBioenergetics11mTORIntegratesNutrientSignalingmTORsensesavailabilityofaminoacids,metabolicfuel,andenergy1Nutrientsandenergystoresareessentialforproteinsynthesis,cellgrowth,proliferation,andsurvival1,2,3mTORactivationsupportsgrowthandsurvivalbyincreasingcellaccesstonutrientsandmetabolicfuels4mTORGrowthSignalingPI3KAktTSC2↑GlucoseTSC1AMPKAminoAcids↑ATP↓Glucose↓ATPCellGrowth&ProliferationProteinSynthesisAngiogenesisBioenergetics12mTORPathwayRegulatesBioenergeticsBioenergeticsreferstonutrientutilizationandmetabolismmTORsensesnutrientandenergyavailabilityinacellmTORpathwayactivationcontrolsbioenergeticsbyincreasingnutrienttransporterexpressionandproductionofangiogenicgrowthfactorsmTORpathwayactivationcontrolsbioenergeticsbyenablingtheinfluxofglucose,aminoacids,andotherimportantmoleculesthataremetabolicfuelsusedtogenerateATPTargetingthemTORpathwaycanimpactthebioenergeticsofthecell13mTORPathwayisDeregulatedbyMutationsinCancerNormalcellgrowth,proliferation,andmetabolismaremaintainedbyanumberofmTORregulators1,2RegulatorsofmTORactivitymTORactivatingmTORdeactivatingDeregulationofmTORcanresultinlossofgrowthcontrolandmetabolism1,3MutationsinthemTORpathwayhavebeenlinkedtospecificcancers4PTENTSC2TSC1mTORCellGrowth&ProliferationAngiogenesisProteinSynthesisBioenergeticsAktPI3KERAblRasRasEGFIGFNutrientsVEGFGrowthSignalingCancerCell1415mTORPathwayisDeregulatedinManyCancersBrainOralSCCBreastPancreasColonUterusProstateSkinOvaryBloodLungThyroidSarcomaKidney16mTORPathwayisDeregulatedinSelectCancersBreastNETColonLungKidneyp-Akt,42%16PI3K,18%–26%27,28PTEN,15%–41%25HER2,30%–36%26,27TSC1/TSC231,32IGF-1/IGF-1R33VHL34p-Akt,46%15PI3K,20%–32%13,41PTEN,35%41Ras,50%12EGFR,70%42p-Akt,23%–50%18PTEN,24%22Ras,30%12EGFR,32%–60%1TSC1/TSC240p-Akt,38%38PTEN,31%39TGFa/TGFb1,60%–100%35VHL,30%–50%36,37IGF-1/IGF-IR,39%-69%9%Incidenceofmutationinselectcancer17mTORActivationSupportsCancerCellGrowthCancercellshavederegulatedgrowthKeyproteinsareregulatedbymTORactivation:–Cellcycleregulators1–Proangiogenicfactors2–Aminoacidandglucosetransporters3,4mTORactivationsupportscancercellgrowthbystimulatingthesynthesisofproteinsimportantforcellgrowth,angiogenesis,nutrientuptake,andmetabolismNutrientsAngio-genesisNutrientUptake&MetabolismGlut1LAT1CellGrowthmTORProteinSynthesisGrowthSignaling4E-BP1S6S6K1elF-4EHIF-1aCyclinD18mTORmTORActivatesCellCycleProgressionIsraelsandIsraels.Oncologist.2000;5:510-513,withpermission.RestrictionpointG2MSG1CyclinD1ProteinSynthesis19mTORPathwayActivationPromotesAngiogenesisSecretionofAngiogenicGrowthFactorsAngiogenesisenablescancercellsaccesstogrowthfactors,nutrientandenergyresources1mTORactivationelevatesproteinsynthesisofHIF-1aandHIF-2a2HIFturnsonseveralhypoxicstressgenesincludingVEGFandPDGF-b3Cancercellssecretetheproangiogenicfactorsthatpromotetheformationofnewvessels1,4,5HIF-1/2mTORHypoxicStressGenesProteinSynthesisAngiogenicFactorsSecretionVHL20mTORPathwayActivationPromotesAngiogenesisGrowthControlofVascularCellsVascularCellGrowthAktPI3KVEGFRPDGFR-bmTORVEGFPDGFTumorAngiogenesisHIF-1/2VHLmTORProteinSynthesisHypoxicStressGenesAngiogenicGrowthFactorsTumorCancerCellVascularPericyteEndothelialCe