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

• Published in: Carcinogenesis (New York) Vol. 25; no. 1; pp. 37 - 45
• Main Authors: Tessner, Teresa G., Muhale, Filipe, Schloemann, Suzanne, Cohn, Steven M., Morrison, Aubrey R., Stenson, William F.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2004; Oxford Publishing Limited (England)
• Subjects: Biological and medical sciences; Cells, Cultured; COX; cyclooxygenase; Cyclooxygenase 2; dichlorobenzimidazole; Dinoprostone - biosynthesis; dominant-negative p38α; DRB; Epithelial Cells - enzymology; Epithelial Cells - radiation effects; Gene Expression Regulation, Enzymologic - radiation effects; Humans; IL-1β; interleukin-1β; Isoenzymes - genetics; MAPK; Medical sciences; Membrane Proteins; mitogen-activated protein kinase; Mitogen-Activated Protein Kinases - physiology; p38 Mitogen-Activated Protein Kinases; p38αDN; p38αWT; PGE2; Promoter Regions, Genetic; prostaglandin E2; Prostaglandin-Endoperoxide Synthases - genetics; Radiation therapy and radiosensitizing agent; Transcription, Genetic; Treatment with physical agents; Treatment. General aspects; Tumors; Up-Regulation; wild-type p38α; Ionizing radiation; Regulation(control); Enzyme; Mitogen-activated protein kinase; Mechanism of action; Radiotherapy; In vitro
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgg183

The epithelial cell line I407 up-regulates cyclooxygenase-2 (COX-2) mRNA and protein expression following ionizing radiation exposure. Prostaglandin E2 (PGE2) production is concomitantly up-regulated. 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 p38α (p38αWT) and dominant-negative p38α (p38αDN) 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 p38αWT clones with γ-radiation resulted in increased COX-2 protein levels and PGE2 synthesis similar to treated control-transfected cells. In contrast, the p38αDN clones failed to up-regulate COX-2 protein or increase PGE2 synthesis when irradiated. Exogenous arachidonate did not restore PGE2 synthesis by p38αDN 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. The data demonstrate a crucial role for p38α 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 probably COX-2 up-regulation, since exogenous arachidonate did not restore PGE2 synthesis.