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
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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DOI：
10.1158/0008-5472.can-03-1086
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发表时间：
2004-02-15
期刊：
影响因子：
11.2
通讯作者：
Wu, T
中科院分区：
文献类型：
--
作者：
Han, C;Leng, J;Wu, T
在人胆管癌中，环氧合酶-2（COX-2）的表达增加。但是，COX-2在控制胆管癌细胞生长中的生物学功能和分子机制尚未得到充分确定。这项研究旨在检查COX-2及其抑制剂Celecoxib对人肝内胆管癌细胞生长的直接影响。 COX-2或前列腺素E-2（PGE（2））治疗的过表达增强了人类胆管癌细胞的生长，而这些细胞中COX-2的反义消耗降低了PGE（2）产生并抑制生长。这些发现表明，COX-2介导的PGE（2）在人胆管癌细胞的生长调节中的直接作用。此外，COX-2抑制剂Celecoxib诱导细胞生长的剂量依赖性抑制作用，G（1）-S检查点的细胞周期停滞以及诱导细胞周期蛋白依赖性激酶抑制剂p21（WAF1/CIP1）和P27（KIP1）（KIP1）（KIP1）（KIP1）（KIP1） 。然而，抑制生长所需的高浓度塞来昔布（50 mum），对塞来昔布诱导的抑制细胞生长的不完全保护通过PGE（2）或COX-2过表达抑制细胞的生长，以及COX--的过度表达或反义消耗2未能改变P21（WAF1/CIP1）和P27（KIP1）的水平，表明存在COX-2独立于塞来昔布诱导的胆管癌细胞生长的机制。
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.