title: Selective proapoptotic activity of a secreted recombinant antibody/AIF fusion protein in carcinomas overexpressing HER2.
abstract: Apoptosis-inducing factor (AIF) represents a caspase-independent apoptotic pathway in the cell, and a mitochondrial localization sequence-truncated AIF (AIFDelta1-120) can be relocated from the cytoplasm to the nucleus and exhibit a constitutive proapoptotic activity. Here, we generated a chimeric immuno-AIF protein, which comprised an HER2 antibody, a Pseudomonas exotoxin translocation domain and AIFDelta1-120. Human Jurkat cells transfected with the immuno-AIF gene could express and secrete the chimeric protein, which selectively recognized HER2-overexpressing tumor cells and was endocytosed. Subsequent cleavage of truncated AIF from immuno-AIF and its release from the internalized vesicles resulted in apoptosis of tumor cells. Intramuscular injection of the immuno-AIF gene caused significant suppression of tumors and substantially prolonged mice survival in an HER2-overexpressing xenograft tumor model. Our study demonstrates the feasibility of the immuno-AIF gene as a novel approach to treating cancers that overexpress HER2.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, China.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Yu
authors.forename: L-T
authors.initials: LT
authors.lastname: Jia
authors.forename: Y-L
authors.initials: YL
authors.lastname: Meng
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: X-C
authors.initials: XC
authors.lastname: Qiu
authors.forename: Y-M
authors.initials: YM
authors.lastname: Xu
authors.forename: W-H
authors.initials: WH
authors.lastname: Wen
authors.forename: L-B
authors.initials: LB
authors.lastname: Yao
authors.forename: D-M
authors.initials: DM
authors.lastname: Fan
authors.forename: B-Q
authors.initials: BQ
authors.lastname: Jin
authors.forename: S-Y
authors.initials: SY
authors.lastname: Chen
authors.forename: A-G
authors.initials: AG
authors.lastname: Yang
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics; D000906:Antibodies / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D051033:Apoptosis Inducing Factor / Q000235:genetics*; D001427:Bacterial Toxins / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D005098:Exotoxins / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D019169:Jurkat Cells; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods; D037521:Virulence Factors / Q000235:genetics; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000906:Antibodies; D051033:Apoptosis Inducing Factor; D001427:Bacterial Toxins; D005098:Exotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C494829:AIFM1 protein, human