The role of nitric oxide in cancer

(整期优先)网络出版时间:2002-05-15
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Nitricoxide(NO)isapleiotropicregulator,criticaltonumerousbiologicalprocesses,includingva-sodilatation,neurotransmissionandmacrophage-mediatedimmunity.Thefamilyofnitricoxidesynthases(NOS)comprisesinducibleNOS(iNOS),endothelialNOS(eNOS),andneuronalNOS(nNOS).Interest-ingly,variousstudieshaveshownthatallthreeisoformscanbeinvolvedinpromotingorinhibitingtheetiologyofcancer.NOSactivityhasbeendetectedintumourcellsofvarioushistogeneticoriginsandhasbeenassociatedwithtumourgrade,proliferationrateandexpressionofimportantsignalingcomponentsassociatedwithcancerdevelopmentsuchastheoestrogenreceptor.ItappearsthathighlevelsofNOSexpression(forexample,generatedbyactivatedmacrophages)maybecytostaticorcytotoxicfortumorcells,whereaslowlevelactivitycanhavetheoppositeeffectandpromotetumourgrowth.Paradoxicallytherefore,NO(andrelatedreactivenitrogenspecies)mayhavebothgenotoxicandangiogenicproperties.IncreasedNO-generationinacellmayselectmutantp53cellsandcontributetotumourangiogenesisbyupregulatingVEGF.Inaddition,NOmaymodulatetumourDNArepairmechanismsbyupregulatingp53,poly(ADP-ribose)polymerase(PARP)andtheDNA-dependentproteinkinase(DNA-PK).Anunderstand-ingatthemolecularleveloftheroleofNOincancerwillhaveprofoundtherapeuticimplicationsforthediagnosisandtreatmentofdisease.