Tumor-specific gene expression using the survivin promoter is further increased by hypoxia

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 0 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.

Comparative evaluation of survivin, midkine, and CXCR4 promoters for transcriptional targeting of glioma gene therapy

“…[39][40][41] The expression of this gene correlates with grade and is present in 90% of glioblastomas. The activity of this promoter is enhanced by hypoxia, 42 commonly found in rapidly growing tumors like high grade gliomas. Survivin seems to play an important role in the oncogenesis and progression of these tumors.…”

Antisense Smo under the control of the PTCH1 promoter delivered by an adenoviral vector inhibits the growth of human pancreatic cancer

“…25,26 In this study, we used the PTCH1 gene promoter to construct a transgenic vector. It has been recently reported that there are seven alternative first exons of PTCH1 (exon 1a, exon 1a 0 , exon 1b, exon 1c, exon 1c 0 , exon 1d and exon 1e), which are differentially regulated by independent promoters in various normal and tumor tissues.…”

Hypoxia Response Elements Can Cause the Overexpression of the BAX mRNA Under Hypoxic Condition

“…Generally, the results of this study show that HRE sequences plays an important role in expression of its upstream genes in hypoxic conditions, which is a common phenomenon of solid tumors (33). Based on this condition, HRE sequence can be considered as a desirable way in targeting of cancer cells for gene therapy.…”