The cyclo-oxygenase 2 promoter is induced in nontarget cells following adenovirus infection, but an AU-rich 3′-untranslated region destabilization element can increase specificity
Article first published online: 14 MAR 2008
Copyright © 2008 John Wiley & Sons, Ltd.
The Journal of Gene Medicine
Volume 10, Issue 7, pages 744–753, July 2008
How to Cite
Särkioja, M., Hakkarainen, T., Eriksson, M., Ristimäki, A., Desmond, R. A., Kanerva, A. and Hemminki, A. (2008), The cyclo-oxygenase 2 promoter is induced in nontarget cells following adenovirus infection, but an AU-rich 3′-untranslated region destabilization element can increase specificity. J. Gene Med., 10: 744–753. doi: 10.1002/jgm.1193
- Issue published online: 16 JUN 2008
- Article first published online: 14 MAR 2008
- Manuscript Accepted: 18 FEB 2008
- Manuscript Revised: 21 DEC 2007
- Manuscript Received: 18 JUL 2007
- Emil Aaltonen Foundation
- EU FP6 THERADPOX and APOTHERAPY, HUCH Research Funds (EVO)
- Sigrid Juselius Foundation
- Academy of Finland
- Finnish Cancer Society
- University of Helsinki
- Biocentrum Helsinki
- Finnish Oncology Association
- Research and Science Foundation of Farmos
- Jalmari ja Rauha Ahokas Foundation
- cancer gene therapy;
- cyclo-oxygenase 2;
- AU rich element
Cyclo-oxygenase 2 (Cox-2) is expressed in many types of tumors, but typically undetectable in normal tissues. However, Cox-2 is known to be induced following infection by many microbial agents, which might threaten the tumor selectivity of the Cox-2 promoter in the context of virotherapy or viral gene delivery. Cox-2 expression is regulated in part post-transcriptionally by stimulation or inhibition of mRNA degradation by 3′-untranslated region (3′-UTR) AU-rich elements. In the present study, we investigated the induction of the Cox-2 promoter both in normal and tumor cells after adenovirus infection and explored the utility of AU-rich elements for regaining promoter selectivity.
Nontumor and tumor cells were transfected in vitro and in vivo with plasmids containing the Cox-2 or cytomegalovirus immediate early promoter driving luciferase (with or without 3′-UTR elements) followed by adenoviral infection. Selectivity and activity of the promoters and 3′-UTR elements were analysed by luciferase assay and in-vivo imaging.
The Cox-2 promoter was induced in both normal and tumor cells following infection with E1 containing replicative adenoviruses but not in the absence of E1. Utilization of AU-rich elements counteracted promoter induction in vitro and in vivo in nonmalignant cells but not in cancer cells, thus increasing the selectivity of the approach ten-fold without loss of potency.
Adenoviral infection induces the Cox-2 promoter in normal and tumor cells, which might compromise specificity of the promoter. Utilization of AU-rich destabilization elements can rescue the tumor selectivity of the promoter. Copyright © 2008 John Wiley & Sons, Ltd.