ColorectalTumorsRequireNUAK1forProtectionfromOxidativeStressJenniferPort1,NathiyaMuthalagu2,MeeraRaja1,FatihCeteci2,TizianaMonteverde1,BjörnKruspig1,AnnHedley2,GabrielaKalna2,SergioLilla2,LisaNeilson2,MartinaBrucoli1,KatarinaGyuraszova1,JacquelineTait-Mulder1,MokdadMezna3,SilvijaSvambaryte1,AmyBryson1,DavidSumpton2,AllanMcVie1,ColinNixon2,MartinDrysdale3,HiroyasuEsumi4,GraemeI.Murray5,OwenJ.Sansom1,2,SaraR.Zanivan1,2,andDanielJ.Murphy1,2ReseaRchaRticleCancerResearch.onDecember28,2018.©2018AmericanAssociationforcancerdiscovery.aacrjournals.orgDownloadedfromPublishedOnlineFirstMarch2,2018;DOI:10.1158/2159-8290.CD-17-0533May2018CANCERDISCOVERY|633aBstRactExploitingoxidativestresshasrecentlyemergedasaplausiblestrategyfortreat-mentofhumancancer,andantioxidantdefensesareimplicatedinresistancetochemotherapyandradiotherapy.Targetedsuppressionofantioxidantdefensescouldthusbroadlyimprovetherapeuticoutcomes.Here,weidentifytheAMPK-relatedkinaseNUAK1asakeycomponentoftheantioxidantstressresponsepathwayandrevealaspecificrequirementforthisroleofNUAK1incolorectalcancer.WeshowthatNUAK1isactivatedbyoxidativestressandthatthisactivationisrequiredtofacilitatenuclearimportoftheantioxidantmasterregulatorNRF2:ActivationofNUAK1coordinatesPP1βinhibitionwithAKTactivationinordertosuppressGSK3β-dependentinhibitionofNRF2nuclearimport.DeletionofNUAK1suppressesformationofcolorectaltumors,whereasacutedepletionofNUAK1inducesregressionofpreexistingautochthonoustumors.Importantly,elevatedexpressionofNUAK1inhumancolorectalcancerisassociatedwithmoreaggressivediseaseandreducedoverallsurvival.SIGNIFICANCE:ThisworkidentifiesNUAK1asakeyfacilitatoroftheadaptiveantioxidantresponsethatisassociatedwithaggressivediseaseandworseoutcomeinhumancolorectalcancer.OurdatasuggestthattransientNUAK1inhibitionmayprovideasafeandeffectivemeansfortreatmentofhumancolorectalcancerviadisruptionofintrinsicantioxidantdefenses.CancerDiscov;8(5);632–47.©2018AACR.1InstituteofCancerSciences,UniversityofGlasgow,Glasgow,UK.2CRUK...
