Apigenin Sensitizes Prostate Cancer Cells to Apo2LTRAIL by Targeting Adenine Nucleotide Translocase-2.docVIP

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Apigenin Sensitizes Prostate Cancer Cells to Apo2LTRAIL by Targeting Adenine Nucleotide Translocase-2.doc

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Apigenin Sensitizes Prostate Cancer Cells to Apo2LTRAIL by Targeting Adenine Nucleotide Translocase-2

ApigeninSensitizesProstateCancerCellstoApo2L/TRAIL byTargetingAdenineNucleotideTranslocase-2 MasakatsuOishi1,2.,YosukeIizumi1.,TomoyukiTaniguchi1,WakanaGoi1,TsuneharuMiki2, ToshiyukiSakai1* 1DepartmentofMolecular-TargetingCancerPrevention,GraduateSchoolofMedicalScience,KyotoPrefecturalUniversityofMedicine,Kawaramachi-Hirokoji,Kamigyo- ku,Kyoto,Japan,2DepartmentofUrology,GraduateSchoolofMedicalScience,KyotoPrefecturalUniversityofMedicine,Kawaramachi-Hirokoji,Kamigyo-ku,Kyoto,Japan Abstract Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent.RecombinanthumanApo2L/TRAILhasbeenunderclinicaltrials,whereasvariouskindsofmalignanttumorshave resistancetoApo2L/TRAIL.Weandothershaveshownthatseveralanticanceragentsandflavonoidsovercomeresistanceto Apo2L/TRAILbyupregulatingdeathreceptor5(DR5)inmalignanttumorcells.However,themechanismsbywhichthese compoundsinduceDR5expressionremainunknown.Hereweshowthatthedietaryflavonoidapigeninbindsandinhibits adeninenucleotidetranslocase-2(ANT2),resultinginenhancementofApo2L/TRAIL-inducedapoptosisbyupregulationof DR5. Apigenin and genistein, which are major flavonoids, enhanced Apo2L/TRAIL-induced apoptosis in cancer cells. ApigenininducedDR5expression,butgenisteindidnot.Usingourmethodidentifyingthedirecttargetsofflavonoids,we comparedthebindingproteinsofapigeninwiththoseofgenistein.WediscoveredthatANT2wasatargetofapigenin,but notgenistein.Similarlytoapigenin,knockdownofANT2enhancedApo2L/TRAIL-inducedapoptosisbyupregulatingDR5 expression at the post-transcriptional level. Moreover, silencing of ANT2 attenuated the enhancement of Apo2L/TRAIL- inducedapoptosisbyapigenin.TheseresultssuggestthatapigeninupregulatesDR5andenhancesApo2L/TRAIL-induced apoptosisbybindingandinhibitingANT2.WeproposethatANT2inhibitorsmaycontributetoApo2L/TRAILtherapy. Citation:OishiM,IizumiY,TaniguchiT,GoiW,MikiT,etal.(2013)ApigeninSensitizesProstateCancerCellstoApo2L/TRAILbyTargetingAdenineNucleotid