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Cancer Res. 2004 Feb 15;64(4):1369-76.

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.

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1
Department of Pathology, University of Pittsburgh School of Medicine, Presbyterian University Hospital, 200 Lothrop Street, Pittsburgh, PA 15213, USA.

Abstract

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 micro M) 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.

PMID:
14973068
[Indexed for MEDLINE]
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