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Induction of Cyclo-oxygenase-2 in Non-small Cell Lung Cancer cells by Adenovirus Vector Infection* FREE TO VIEW

Edward A. Hirschowitz, MD, FCCP; Giovanna E. Hidalgo, BS; Dennis E. Doherty, MD, FCCP
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*From the Division of Pulmonary and Critical Care Medicine, Lexington Veterans Affairs Medical Center, University of Kentucky, Chandler Medical Center, Lexington KY.

Correspondence to: Edward A. Hirschowitz, MD, FCCP, Division of Pulmonary and Critical Care Medicine, University of Kentucky, Chandler Medical Center, 800 Rose St, Room MN 614, Lexington, KY 40536; e-mail: eahirs2@pop.uky.edu

Chest. 2002;121(3_suppl):32S. doi:10.1378/chest.121.3_suppl.32S
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Infection of epithelial-derived cells by adenovirus vectors has myriad effects on cellular behavior and function. Some effects are relevant to the desired effect of the encoded transgene and therapeutic goals of gene therapy approach. The current experiments describe the induction of cyclo-oxygenase (COX)-2 protein and prostaglandin (PGE)-2 production by non-small cell lung cancer cells following infection with a first generation (ΔE1, ΔE3) Ad vector. Notably, PGE-2 has been implicated in tumor-induced immunosuppression. ΔE1, ΔE3-Ad vector infection of non-small cell lung cancer cell line NCI-820 induced dose-dependent increases in PGE-2 production (moi10–50). Induction was related to the transgene expressed. Detectable increases in COX-2 protein were seen by Western blot 36 h after infection; these were paralleled by increases in phosphorylation of extracellular signal-related kinase (ERK)-1/2. Selective blockade of ERK with PD98029 reduced constitutive COX-2 expression and prevented induction of PGE-2 following Ad infection. An inhibitor of nuclear factor (NF)-κB translocation to the nucleus, SN50, had no effect on constitutive nor inducible PGE-2 levels. In contrast, Ad vector infection did induce NF-κB activity as measured by an NF-κB luciferase reporter plasmid transfected into cell line NCI-820. Further, UV/psoralen-inactivated vector did not have similar effects on PGE-2, indicating the importance of gene expression. Ad vector infection leads to ERK phosphorylation with parallel increases in COX-2 protein and PGE-2 production. These effects appear unrelated to NF-κB and are dependent on gene expression by the vector. In this context, induction of PGE-2 by Ad vectors may need to be considered when defining targets for immunogene therapy and/or choice of viral vector.

Abbreviations: COX = cyclo-oxygenase; ERK = extracellular signal-related kinase; NF = nuclear factor; PGE = prostaglandin

Supported by Veterans Administration Career Development Award project No. 596–416905007–0001, and from a generous donation from the McDowell Foundation-Papa Johns/Valvano fund for cancer research.




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