ReviewOxidativeStressinCancerJohnD.Hayes,1,*AlbenaT.Dinkova-Kostova,1,2andKennethD.Tew31DivisionofCellularMedicine,JacquiWoodCancerCentre,NinewellsHospitalandMedicalSchool,UniversityofDundee,DundeeDD19SY,UK,Scotland2DepartmentofPharmacologyandMolecularSciencesandDepartmentofMedicine,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD21205,USA3DepartmentofCellandMolecularPharmacology,MedicalUniversityofSouthCarolina,Charleston,SC29425,USA*Correspondence:j.d.hayes@dundee.ac.ukhttps://doi.org/10.1016/j.ccell.2020.06.001Contingentuponconcentration,reactiveoxygenspecies(ROS)influencecancerevolutioninapparentlycon-tradictoryways,eitherinitiating/stimulatingtumorigenesisandsupportingtransformation/proliferationofcancercellsorcausingcelldeath.ToaccommodatehighROSlevels,tumorcellsmodifysulfur-basedmeta-bolism,NADPHgeneration,andtheactivityofantioxidanttranscriptionfactors.Duringinitiation,geneticchangesenablecellsurvivalunderhighROSlevelsbyactivatingantioxidanttranscriptionfactorsorincreasingNADPHviathepentosephosphatepathway(PPP).Duringprogressionandmetastasis,tumorcellsadapttooxidativestressbyincreasingNADPHinvariousways,includingactivationofAMPK,thePPP,andreductiveglutamineandfolatemetabolism.IntroductionOxidativestress,definedasarelativeexcessofreactiveoxygenspecies(ROS)whencomparedwithantioxidants,hasbeenlinkedtoneurodegenerativedisease,cardiovasculardisease,diabetesmellitus,andmanyotherpathologies(Sies,2015).Theseassociationsemphasizethatabalancemustbestruckbe-tweentherelativeabundanceofROSandantioxidants.Cellspossesscomplexbiochemicalandgeneticmechanismstomaintainsuchabalance,anditisclearthattheirperturbationcanhaveprofoundpathophysiologicalconsequences.Cancercellsexhibitaberrantredoxhomeostasis,butwhileROSarepro-tumorigenic,highROSlevelsarecytotoxic(Reczeketal.,2017).Specifically,hyperproliferationoftumorcellsisaccompaniedbyhighROSproduction,buttheyareadaptedtothriveunderconditionswherethisoxidativeburdenpushesredoxbalanceawayfromareducedstate;tumorcellsachievethi...
