Addressing Reported Pro-Apoptotic Functions of NF-κB Targeted Inhibition of Canonical NF-κB Enhances the Apoptotic Effects of Doxorubicin 英文参考文献.docVIP

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Addressing Reported Pro-Apoptotic Functions of NF-κB Targeted Inhibition of Canonical NF-κB Enhances the Apoptotic Effects of Doxorubicin 英文参考文献.doc

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Addressing Reported Pro-Apoptotic Functions of NF-κB Targeted Inhibition of Canonical NF-κB Enhances the Apoptotic Effects of Doxorubicin 英文参考文献

AddressingReportedPro-ApoptoticFunctionsofNF-kB: TargetedInhibitionofCanonicalNF-kBEnhancesthe ApoptoticEffectsofDoxorubicin BrianK.Bednarski1,2,AlbertS.Baldwin,Jr.1,HongJinKim1,2* 1LinebergerComprehensiveCancerCenter,UniversityofNorthCarolina,ChapelHill,NorthCarolina,UnitedStatesofAmerica,2DepartmentofSurgery,Universityof NorthCarolina,ChapelHill,NorthCarolina,UnitedStatesofAmerica Abstract TheabilityofthetranscriptionfactorNF-kBtoupregulateanti-apoptoticproteinshasbeenlinkedtothechemoresistanceof solidtumorstostandardchemotherapy.Incontrast,recentstudieshaveproposedthat,inresponsetodoxorubicin,NF-kB can be pro-apoptotic through repression of anti-apoptotic target genes. However, there is little evidence analyzing the outcomeofNF-kBinhibitiononthecytotoxicityofdoxorubicininstudiesdescribingpro-apoptoticNF-kBactivity.Inthis study,wefurthercharacterizetheactivationofNF-kBinresponsetodoxorubicinandevaluateitsroleinchemotherapy- induced cell death in sarcoma cells where NF-kB is reported to be pro-apoptotic. Doxorubicin treatment in U2OS cells inducedcanonicalNF-kBactivityasevidencedbyincreasednuclearaccumulationofphosphorylatedp65atserine536and increasedDNA–bindingactivity.Co-treatmentwithasmallmoleculeIKKbinhibitor,CompoundA,abrogatedthisresponse. RT–PCR evaluation of anti-apoptotic gene expression revealed that doxorubicin-induced transcription of cIAP2 was inhibited by Compound A, while doxorubicin-induced repression of other anti-apoptotic genes was unaffected by Compound A or siRNA to p65. Furthermore, the combination of doxorubicin and canonical NF-kB inhibition with Compound A or siRNA to p65 resulted in decreased cell viability measured by trypan blue staining and MTS assay and increased apoptosis measured by cleaved poly (ADP-ribose) polymerase and cleaved caspase 3 when compared to doxorubicin alone. Our results demonstrate that doxorubicin-induced canonical NF-kB activity associated with phosphorylated p65 is anti-apoptotic in its function and that dox