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Cyclooxygenase-2 Promotes Human Cholangiocarcinoma Growth

Evidence for Cyclooxygenase-2-Independent Mechanism in Celecoxib-Mediated Induction of p21^waf1/cip1 and p27^kip1 and Cell Cycle Arrest

¹ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and² Department of Pathology, Nanjing Medical University, Nanjing, China

The expression of cyclooxygenase-2 (COX-2) is increased in human cholangiocarcinoma. However, the biologic function and molecular mechanisms of COX-2 in the control of cholangiocarcinoma cell growth have not been well established. This study was designed to examine the direct effect of COX-2 and its inhibitor celecoxib on the growth of human intrahepatic cholangiocarcinoma cells. Overexpression of COX-2 or treatment with prostaglandin E₂ (PGE₂) enhanced human cholangiocarcinoma cell growth, whereas antisense depletion of COX-2 in these cells decreased PGE₂ production and inhibited growth. These findings demonstrate a direct role of COX-2-mediated PGE₂ in the growth regulation of human cholangiocarcinoma cells. Furthermore, the COX-2 inhibitor celecoxib induced a dose-dependent inhibition of cell growth, cell cycle arrest at the G₁-S checkpoint, and induction of cyclin-dependent kinase inhibitors p21^waf1/cip1 and p27^kip1. However, the high concentration of celecoxib (50 µM) required for inhibition of growth, the incomplete protection of celecoxib-induced inhibition of cell growth by PGE₂ or COX-2 overexpression, and the fact that overexpression or antisense depletion of COX-2 failed to alter the level of p21^waf1/cip1 and p27^kip1 indicate the existence of a COX-2-independent mechanism in celecoxib-induced inhibition of cholangiocarcinoma cell growth.

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