Sensitivity to TOP2 Targeting Chemotherapeutics Is Regulated by Oct1 and FILIP1L 英文参考文献.docVIP

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Sensitivity to TOP2 Targeting Chemotherapeutics Is Regulated by Oct1 and FILIP1L 英文参考文献.doc

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Sensitivity to TOP2 Targeting Chemotherapeutics Is Regulated by Oct1 and FILIP1L 英文参考文献

SensitivitytoTOP2TargetingChemotherapeuticsIs RegulatedbyOct1andFILIP1L HuaruiLu,TimothyC.Hallstrom* DepartmentofPediatrics,UniversityofMinnesota,Minneapolis,Minnesota,UnitedStatesofAmerica Abstract TopoisomeraseII(TOP2)targetingdrugslikedoxorubicinandetoposidearefrontlinechemotherapeuticsforawidevariety ofsolidandhematologicalmalignancies,includingbreastandovarianadenocarcinomas,lungcancers,softtissuesarcomas, leukemiasandlymphomas.TheseagentscauseablockinDNAreplicationleadingtoapronouncedDNAdamageresponse andinitiationofapoptoticprograms.Resistancetotheseagentsiscommon,however,andelucidationofthemechanisms causingresistancetotherapycouldshedlightonstrategiestoreducethefrequencyofineffectivetreatments.Toexplore these mechanisms, we utilized an unbiased shRNA screen to identify genes that regulate cell death in response to doxorubicin treatment. We identified the Filamin A interacting protein 1-like (FILIP1L) gene as a crucial mediator of apoptosis triggered by doxorubicin. FILIP1L shares significant similarity with bacterial SbcC, an ATPase involved in DNA repair.FILIP1LwasoriginallydescribedasDOC1,or‘‘down-regulatedinovariancancer’’andhassincebeenshowntobe downregulatedinawidevarietyofhuman tumors.FILIP1L levelsincrease markedly throughtranscriptional mechanisms followingtreatmentwithdoxorubicinandotherTOP2poisons,includingetoposideandmitoxantrone,butnotbytheTOP2 catalyticinhibitorsmerbaroneordexrazoxane(ICRF187),orbyUVirradiation.ThisinductionrequirestheactionoftheOCT1 transcriptionfactor,whichrelocalizestotheFILIP1Lpromoterandfacilitatesitsexpressionfollowingdoxorubicintreatment. Our findings suggest that the FILIP1L expression status in tumors may influence the response to anti-TOP2 chemotherapeutics. Citation: Lu H, HallstromTC (2012) Sensitivity toTOP2 TargetingChemotherapeutics IsRegulatedby Oct1 andFILIP1L. PLoSONE 7(8): e42921. doi:10.1371/ journal.pone.0042921 Editor:YoshiakiTsuji,NorthCarolinaStateUniversity,UnitedStatesofAmerica ReceivedApril24,