Synergistic Regulation of COX-2 Expression by Bombesin and Transforming Growth Factor-β

Overexpression of cyclooxygenase-2 (COX-2), an inducible enzyme regulating prostaglandin release, is mechanistically linked to the development, growth, and spread of gastrointestinal (GI) cancers. GI peptide bombesin (BBS) was reported to stimulate COX-2 gene expression. Here we show that TGF-β1 dramatically enhances the BBS-induced expression of COX-2 mRNA and protein, and the release of PGE2 in the model rat intestinal epithelial cell (RIE-1) line. The synergistic increase in COX-2 levels results from a combination of enhanced COX-2 transcription and reduced mRNA degradation. BBS, but not TGF-β1, stimulated COX-2 promoter activity, and TGF-β1 enhanced COX-2 mRNA stability through a p38 MAPK -dependent pathway. The synergistic regulation of COX-2 expression by TGF-β1 and BBS may contribute to the upregulation of COX-2 in GI cancers.