Activator protein-1 transcription factor mediates bombesin-stimulated cyclooxygenase-2 expression in intestinal epithelial cells

Colorectal carcinogenesis is a complex, multistep process involving genetic alterations and progressive changes in signaling pathways regulating intes tinal epithelial cell proliferation, differentiation, and apoptosis, Althou gh cyclooxygenase-2 (COX-2), gastrin-releasing peptide (GRP), and its recep tor, GRP-R, are not normally expressed by the epithelial cells lining the h uman colon, the levels of all three proteins are aberrantly overexpressed i n premalignant adenomatous polyps and colorectal carcinomas of humans. Over expression of these proteins is associated with altered epithelial cell gro wth, adhesion, and tumor cell invasiveness, both in vitro and in vivo; howe ver, a mechanistic link between GRP-R-mediated signaling pathways and incre ased COX-2 overexpression has not been established, We report that bombesin , a homolog of GRP, potently stimulates the expression of COX-2 mRNA and pr otein as well as the release of prostaglandin E-2 from a rat intestinal epi thelial cell line engineered to express GRP-R. Bombesin stimulation of COX- 2 expression requires an increase in [Ca2+](i), activation of extracellular signal-regulated kinase (ERR)-1 and -2 and p38(MAPK), and increased activa tion and expression of the transcription factors Elk-1, ATF-S, c-Fos, and c -Jun, These data suggest that the expression of GRP-R in intestinal epithel ial cells may play a role in carcinogenesis by stimulating COX-2 overexpres sion through an activator protein-1-dependent pathway.