Anti-Tumoral Effect of the Mitochondrial Target Domain of Noxa Delivered by an Engineered Salmonella typhimurium.docVIP

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Anti-Tumoral Effect of the Mitochondrial Target Domain of Noxa Delivered by an Engineered Salmonella typhimurium.doc

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Anti-Tumoral Effect of the Mitochondrial Target Domain of Noxa Delivered by an Engineered Salmonella typhimurium

Anti-TumoralEffectoftheMitochondrialTargetDomain ofNoxaDeliveredbyanEngineeredSalmonella typhimurium Jae-HoJeong1,KwangsooKim1,DaejinLim1,KwangjoonJeong1,YeongjinHong1,VuH.Nguyen2, Tae-HyoungKim3,SangryeolRyu4,Jeong-ALim4,JaeIlKim5,Geun-JoongKim6,SunChangKim7, Jung-JoonMin2*,HyonE.Choy1* 1Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea, 2Department of Nuclear Medicine, Chonnam National UniversityMedicalSchool,Gwangju,RepublicofKorea,3DepartmentofBiochemistry,ChosunUniversityMedicalSchool,Gwangju,RepublicofKorea,4Departmentof FoodandAnimalBiotechnology,SeoulNationalUniversity,Seoul,Korea,5SchoolofLifeScience,GwangjuInstituteofScienceandTechnology(GIST),Gwangju,Republic ofKorea, 6Department ofBiological Sciences,CollegeofNatural Sciences,ChonnamNationalUniversity, Yongbong-Dong, Buk-Gu, Gwangju, Korea, 7Department of BiologicalSciences,KoreaAdvancedInstituteofScienceandTechnology,Daejeon,Korea Abstract Bacterial cancer therapy relies on the fact that several bacterial species are capable of targeting tumor tissue and that bacteria can be genetically engineered to selectively deliver therapeutic proteins of interest to the targeted tumors. However,thechallengeofbacterialcancertherapyisthereleaseofthetherapeuticproteinsfromthebacteriaandentryof the proteins into tumor cells. This study employed an attenuated Salmonella typhimurium to selectively deliver the mitochondrialtargetingdomainofNoxa(MTD)asapotentialtherapeuticcargoprotein,andexamineditsanti-cancereffect. ToreleaseMTDfromthebacteria,anovelbacteriallysissystemofphageoriginwasdeployed.TofacilitatetheentryofMTD into the tumor cells, the MTD was fused to DS4.3, a novel cell-penetrating peptide (CPP) derived from a voltage-gated potassiumchannel(Kv2.1).ThegeneencodingDS4.3-MTDandthephagelysisgeneswereplacedunderthecontrolofPBAD, apromoteractivatedbyL-arabinose.WedemonstratedthatDS4.3-MTDchimericmoleculesexpressedbytheSalmonellae wereanti-tumoralinculturedtumorce