Introduction: Caudal homeobox 2 (CDX2), a transcription factor involved in normal intestinal development, is thought to be the key factor responsible for the intestinal phenotype and possibly Barrett’s esophagus. We have previously shown that deoxycholic acid (DCA) induces CDX2 mRNA which may occur in part through transactivation of the epidermal growth factor receptor (EGFR). This study aimed to further our understanding of the intracellular signaling events triggered by bile acid induced receptor activation. Methods: Human Barrett’s associated esophageal adenocarcinoma cells (OE19) were incubated with increasing concentrations of DCA for up to 8h w/wo an EGFR tyrosine kinase inhibitor (tyrphostin, AG1478), antibody against the ligand binding site of EGFR (Mab528), a PI3K inhibitor (wortmanin) or a PKC pan inhibitor (chelerythrine). Levels of CDX2 mRNA were determined by real-time PCR and total and phosphorylated EGFR, Akt, Erk and PKC protein were determined by Western blot analysis. Results: Small basal amounts of CDX2 mRNA and protein were detected in the cells. Maximum CDX2 mRNA was induced by 4h treatment with 100μM DCA (3.35±0.32 fold, p<0.01, n=4). PKC inhibition (chelerythrine) decreased DCA induced CDX2 mRNA expression by one half (p<0.001, n=3). DCA induced PKC phosphorylation (2.8± 0.5 fold, p<0.001, n=4), was reduced by half by chelerythrine inhibition (0.56±0.15, p<0.001, n=4). Basal levels of CDX2 protein were not increased by DCA treatment, but were reduced relative to control (0.18±0.05 of basal, p<0.0001, n=5) by PKC inhibition. DCA induced CDX2 mRNA was not affected by EGFR receptor (Mab528) or tyrosine kinase (AG1478) blockade or PI3K inhibition (wortmanin). Further, DCA induced phosphorylation of EGFR, Erk and Akt was eliminated by AG1478, but not by chelerythrine, while PI3k inhibition abolished only Akt phosphorylation.Conclusion: Taken together these findings suggest that in this moderately differentiated esophageal adenocarcinoma cell line both basal and bile acid induced CDX2 message and protein are controlled via activation of PKC without involvement of EGFR, Erk and PI3K pathways. Given previous findings it appears that the origin and degree of cell differentiation may determine the pathways controlling CDX2 expression and should be taken into account when designing putative therapy.