Selective proapoptotic activity of a secreted recombinant antibody/AIF fusion protein in carcinomas overexpressing HER2.
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.
Yu
C-J
CJ
State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, China.
Jia
L-T
LT
Meng
Y-L
YL
Zhao
J
J
Zhang
Y
Y
Qiu
X-C
XC
Xu
Y-M
YM
Wen
W-H
WH
Yao
L-B
LB
Fan
D-M
DM
Jin
B-Q
BQ
Chen
S-Y
SY
Yang
A-G
AG
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
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