Abstract
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.
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Acknowledgements
We express our sincere thanks to Dr Bert Vogelstein at Johns Hopkins University for pAdtrackCMV and p-shuttle vectors, and Dr Emad S Alnemri at Thomas Jefferson University for providing us with the reverse caspase-3 gene. This research project is supported in part by the Breast Cancer Research Program of Avon Foundation (to LY), NIH Grants # CA95643 (to LY), CA80017 (to LY), CA87830 NS41403. CA86335 (to EGVM) and The Brain Tumor Society (to EGVM and DEP).
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Yang, L., Cao, Z., Li, F. et al. Tumor-specific gene expression using the survivin promoter is further increased by hypoxia. Gene Ther 11, 1215–1223 (2004). https://doi.org/10.1038/sj.gt.3302280
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DOI: https://doi.org/10.1038/sj.gt.3302280
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