Tumor-specific gene expression using the survivin promoter is further increased by hypoxia.
Increasing evidence indicates that survivin, an inhibitor of apoptosis protein (IAP), is expressed in human cancer cells but is absent from most normal adult tissues. Here, we examined the feasibility of using a survivin promoter (Sur-P) to direct therapeutic expression of a proapoptotic gene specifically in human tumor cells. First, we demonstrated that this promoter was highly active in human tumor cells but not in normal cells. Second, we found that Sur-P activity was upregulated by hypoxia in tumor cells. Third, to further enhance this promoter's activity under hypoxia, we added a hypoxia-responsive element (HRE) from the vascular endothelial growth factor gene promoter in its 5' region, and showed that this combination resulted in a further increase in the level of gene expression in hypoxic tumor cells. Finally, we demonstrated that expression of an autocatalytic reverse caspase-3 gene by this promoter specifically induced apoptotic cell death in human tumor cells but not in normal cells. These findings support the use of promoters Sur-P or chimeric HRE-Sur-P for generating novel vectors for cancer gene therapy.
Yang
L
L
Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cao
Z
Z
Li
F
F
Post
D E
DE
Van Meir
E G
EG
Zhong
H
H
Wood
W C
WC
D017209:Apoptosis; D015153:Blotting, Western / Q000379:methods; D001943:Breast Neoplasms / Q000628:therapy; D053148:Caspase 3; D061945:Caspase Inhibitors; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009363:Neoplasm Proteins; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D010190:Pancreatic Neoplasms / Q000628:therapy; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
C107489:BIRC5 protein, human; D061945:Caspase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; C505407:CASP3 protein, human; D053148:Caspase 3