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Carcinogenesis Advance Access published online on September 26, 2003
Carcinogenesis, doi:10.1093/carcin/bgg183
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CANCER BIOLOGY

Ionizing radiation upregulates cyclooxygenase-2 in I407 cells through p38 mitogen-activated protein kinase

Teresa G. Tessner 1*, Filipe Muhale 1, Suzanne Schloemann 1, Steven M. Cohn 2, Aubrey R. Morrison 3, and William F. Stenson 1

1 Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri 63110
2 Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia 22904
3 Department of Medicine and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

* Corresponding author. E-mail: stensnlb{at}im.wustl.edu.

Received 27 March 2003 ; revised 12 August 2003 ; accepted 17 September 2003

Abstract

The epithelial cell line I407 upregulates cyclooxygenase-2 (COX-2) mRNA and protein expression following ionizing radiation exposure. Prostaglandin E2 (PGE2) production is concomitantly upregulated. Irradiation of I407 cells also results in phosphorylation of the p38 mitogen-activated protein kinase and the p38 inhibitor SB203580 abrogates radiation-induced PGE2 synthesis. Wild-type p38{alpha} (p38{alpha}WT) and dominant-negative p38{alpha} (p38{alpha}DN) stable transfectant clones of I407 cells were used to examine the role of the p38 mitogen-activated protein kinase pathway in the events controlling PGE2 synthesis after ionizing radiation. Treatment of p38{alpha}WT clones with {gamma}-radiation resulted in increased COX-2 protein levels and PGE2 synthesis similar to treated control-transfected cells. In contrast, the p38{alpha}DN clones failed to upregulate COX-2 protein or increase PGE2 synthesis when irradiated. Exogenous arachidonate did not restore PGE2 synthesis by p38{alpha}DN cells. Radiation increased COX-2 mRNA stability and the p38 inhibitor SB203580 attenuated COX-2 mRNA stability in irradiated I407 cells. In contrast, irradiation had no effect on transcription from a COX-2 promoter/luciferase reporter plasmid in the presence or absence of SB203580. These data demonstrate a crucial role for p38{alpha} in COX-2 expression and PGE2 synthesis in an irradiated transformed epithelial cell line. Furthermore, they indicate that p38 activity is required at a step distal to arachidonate release, most likely COX-2 upregulation, since exogenous arachidonate did not restore PGE2 synthesis.

radiation, cyclooxygenase-2, p38 MAPK, intestine, cancer
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