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Cyclooxygenase-2–Derived Prostaglandin E₂ Activates β-Catenin in Human Cholangiocarcinoma Cells: Evidence for Inhibition of These Signaling Pathways by 3 Polyunsaturated Fatty Acids

¹ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania and ² Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon, Korea

Requests for reprints: Tong Wu, Department of Pathology, University of Pittsburgh School of Medicine, MUH E-740, 200 Lothrop Street, Pittsburgh, PA 15213. Phone: 412-647-9504; Fax: 412-647-5237; E-mail: wut{at}upmc.edu or Kyu Lim, Department of Biochemistry, College of Medicine, Chungnam National University, Korea. Phone: 42-580-8223; Fax: 42-580-8121; E-mail: kyulim{at}cnu.ac.kr.

Cholangiocarcinoma is a highly malignant neoplasm of the biliary tree. It has a high rate of mortality, and currently, there is no effective chemoprevention and treatment. This study was designed to investigate the potential effect of 3 polyunsaturated fatty acids (3-PUFA) on human cholangiocarcinoma cell growth and to determine their mechanisms of actions. Treatment of three human cholangiocarcinoma cells (CCLP1, HuCCT1, SG231) with two 3-PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), for 12 to 72 h resulted in a dose- and time-dependent inhibition of cell growth; in contrast, arachidonic acid, a 6-PUFA, had no significant effect. The 3-PUFA effect is due to the induction of apoptosis, given that DHA induced the cleaved form of PARP, caspase-3, and caspase-9. DHA and EPA treatment caused dephosphorylation (and hence, the activation) of glycogen synthase kinase-3β (GSK-3β) with a decline of β-catenin protein. Accordingly, DHA treatment also decreased the β-catenin–mediated T cell factor/lymphoid enhancer factor (TCF/LEF) reporter activity, and inhibited the expression of c-Met, a β-catenin–controlled downstream gene implicated in cholangiocarcinogenesis. The GSK-3β inhibitor, SB216763, partially prevented DHA-induced reduction of β-catenin protein and TCF/LEF reporter activity, and restored cell growth, suggesting the involvement of GSK-3β dephosphorylation in 3-PUFA–induced β-catenin degradation. In parallel, DHA treatment also induced the formation of the β-catenin/Axin/GSK-3β binding complex, further leading to β-catenin degradation. Moreover, DHA inhibited the expression of cyclooxygenase-2 (COX-2) and enhanced the expression of 15-hydroxyprostaglandin dehydrogenase, a physiologic COX-2 antagonist, in human cholangiocarcinoma cells. These findings suggest that 3-PUFAs block cholangiocarcinoma cell growth at least in part through inhibition of Wnt/β-catenin and COX-2 signaling pathways. Thus, utilization of 3-PUFAs may represent an effective and safe therapeutic approach for the chemoprevention and treatment of human cholangiocarcinoma. [Cancer Res 2008;68(2):553–60]