Cyclooxygenase-2 promotes human cholangiocarcinoma growth:: Evidence for cyclooxygenase-2-independent mechanism in celecoxib-mediated induction of p21Waf1/cip1 and p27kip1 and cell cycle arrest

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 E-2 (PGE(2)) enhanced human cholangiocarcinoma cell growth, whereas antisense depletion of COX-2 in these cells decreased PGE(2) production and inhibited growth. These findings demonstrate a direct role of COX-2-mediated PGE(2) 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 G(1)-S checkpoint, and induction of cyclin-dependent kinase inhibitors p21(waf1/cip1) and p27(kip1). However, the high concentration of celecoxib (50 mum) required for inhibition of growth, the incomplete protection of celecoxib-induced inhibition of cell growth by PGE(2) 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.