Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 122; no. 4; p. 985
• Main Authors: Yoon, Jung-Hwan, Higuchi, Hajime, Werneburg, Nathan W, Kaufmann, Scott H, Gores, Gregory J
• Format: Journal Article
• Language: English
• Published: United States 01.04.2002
• Subjects: Bile Acids and Salts - pharmacology; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Cyclooxygenase 2; ErbB Receptors - metabolism; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; Isoenzymes - genetics; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; MAP Kinase Signaling System - drug effects; Membrane Proteins; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases; Prostaglandin-Endoperoxide Synthases - genetics; src-Family Kinases - metabolism; Tumor Cells, Cultured
• ISSN: 0016-5085
• DOI: 10.1053/gast.2002.32410

Although bile acids have been implicated in colon cancer development, their role in biliary tract carcinogenesis remains unexplored. Because receptor tyrosine kinases and cyclooxygenase (COX)-2 have been implicated in carcinogenesis, we examined the hypothesis that bile acids modulate these enzymes in KMBC cells, a human cholangiocarcinoma cell line. The effect of bile acids on epidermal growth factor receptor (EGFR) stimulation, mitogen-activated protein kinase (MAPK) activation, and COX-2 expression was evaluated. Bile acids both induced EGFR phosphorylation and enhanced COX-2 protein expression. Bile acid-induced EGFR phosphorylation was associated with subsequent activation of MAPK p42/44, p38, and c-Jun-N-terminal kinase (JNK). The MAPK inhibitors, PD098059 for MAP or extracellular signal-regulated kinase 1, SB203580 for p38, and BAY 37-9751 for Raf-1, blocked COX-2 induction by bile acids. However, inhibition of JNK activity did not block bile acid-mediated COX-2 induction. The results show that EGFR is activated by bile acids and functions to induce COX-2 expression by an MAPK cascade. This induction of COX-2 may participate in the genesis and progression of cholangiocarcinomas.