Dihydroxy bile acids activate the transcription of cyclooxygenase-2

Bile acids, endogenous promoters of gastrointestinal cancer, activate protein kinase C (PKC) and the activator protein-1 (AP-1) transcription factor. Because other activators of PKC and AP-1 induce cyclooxygenase-2 (COX-2), we determined the effects of bile acids on the expression of COX-2 in human esophageal adenocarcinoma cells. Treatment with the dihydroxy bile acids chenodeoxycholate and deoxycholate resulted in an approximately 10-fold increase in the production of prostaglandin E2 (PGE2). Enhanced synthesis of PGE2 was associated with a marked increase in the levels of COX-2 mRNA and protein, with maximal effects at 8-12 and 12-24 h, respectively. In contrast, neither cholic acid nor conjugated bile acids affected the levels of COX-2 or the synthesis of PGE2. Nuclear run-off assays and transient transfections with a human COX-2 promoter construct showed that induction of COX-2 mRNA by chenodeoxycholate and deoxycholate was due to increased transcription. Bile acid-mediated induction of COX-2 was blocked by inhibitors of PKC activity, including calphostin C and staurosporine. Treatment with bile acid enhanced the phosphorylation of c-Jun and increased binding of AP-1 to DNA. These data are important because dihydroxy bile acid-mediated induction of COX-2 may explain, at least in part, the tumor-promoting effects of bile acids.