Journal
GENE THERAPY
Volume 11, Issue 15, Pages 1215-1223Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3302280
Keywords
survivin promoter; reverse caspase-3 gene; hypoxia; hypoxia-responsive element; apoptosis; targeted cancer gene therapy; hypoxia-inducible factor1 (HIF-1)
Categories
Funding
- NCI NIH HHS [R01 CA095643, CA87830, R01 CA095643-01A1, R29 CA080017-04, R29 CA080017, CA95643, R29 CA080017-02, R29 CA080017-03, R29 CA080017-01, R01 CA086335, CA80017, CA86335] Funding Source: Medline
- NINDS NIH HHS [NS41403] Funding Source: Medline
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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 50 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.
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