Epithelial cyclooxygenase-2 expression: A model for pathogenesis of colon cancer

Background Recent studies indicate a close relationship between cyclooxygen se-2 (COX-2) expression and the pathogenesis of colorectal cancer, yet litt le information exists regarding the stimuli and pathways involved in COX-2 expression by the colonic epithelium. We studied the induction of COX-2 in response to such environmental stress as hyperosmolarity and lipopolysaccha ride (LPS) in a human colon cell line. We further investigated the transduc tion cascades mediating COX-2 expression, focusing upon the mitogen-activat ed protein kinase pathways p38 and extracellular signal-regulated kinase (E RK). Materials and methods. Human colon cancer cells (Caco-2) were stimulated wi th increasing concentrations of sodium chloride (NaCl) or LPS. Total protei n was extracted at different time points and subjected to Western blot anal ysis with antibodies to human COX-2, COX-1, or phospho-specific antibodies to ERK and p38. Results. LPS failed to induce COX-2 or COX-1 expression. Hyperosmolarity in duced COX-2 expression by 2 h, with peak levels occurring at 6-8 h. NaCl at 40 and 100 mM induced a 2-fold and more than 50-fold increase in COX-2 exp ression, respectively; COX-1 expression was not affected. Hyperosmolarity i nduced both p38 and ERK activation within 30 min; however, only p38 inhibit ion attenuated osmotic-induced COX-2 expression; inhibition of ERK activati on had no effect. Conclusions. Increase in osmolarity activates p38 and induces COX-2 express ion in the colonic epithelium. The lack of response to LPS is teleologicall y expected of the colonic epithelium that is in constant contact with the f ecal bacteria. This model also pre-diets that an increase in luminal osmola rity in the colon may induce COX-2 and thereby promote a neoplastic phenoty pe. (C) 2001 Academic Press.