Vitro and in vivo effects and mechanisms of celecoxib-induced growth inhibition of human hepatocellular carcinoma cells
Vitro and in vivo effects and mechanisms of celecoxib-induced growth inhibition of human hepatocellular carcinoma cells
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DOI：
10.1158/1078-0432.ccr-05-1044
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发表时间：
2005-11-15
影响因子：
11.5
通讯作者：
Hu, KQ
中科院分区：
文献类型：
--
作者：
Cui, W;Yu, CH;Hu, KQ
目的：环氧合酶-2 (COX-2) 抑制剂会抑制人肝细胞癌细胞的生长，但目前尚不清楚这是否既依赖于 COX-2，又独立于 COX-2。相关机制仍有待确定。本研究旨在探讨塞来昔布对肝癌细胞和移植瘤生长的影响及其相关机制。 实验设计：采用低表达COX-2的PLC/PRF/5和高表达COX-2的HuH7细胞以及荷有肝癌移植瘤的裸鼠，研究塞来昔布对肝癌细胞生长的影响和机制。两种肝细胞癌细胞的生长抑制与两种细胞中前列腺素 E-2 的产生减少和过氧化物酶体增殖物激活受体 γ 的增加有关。添加前列腺素 E2 仅部分抵消了塞来昔布对两种细胞的作用。塞来昔布导致两种细胞中视网膜母细胞瘤磷酸化和 DP1/E2F1 复合物显着减少。塞来昔布导致两种细胞的凋亡和 caspase-3 和 caspase-9 的激活显着增加。在接种HuH7细胞的裸鼠中，塞来昔布导致肝细胞癌异种移植物的频率和平均重量下降。结论：本研究表明，塞来昔布通过以下方式对肝细胞癌细胞和异种移植物产生COX-2依赖性和COX-2非依赖性生长抑制：（a）减少视网膜母细胞瘤磷酸化和DP1/E2F1复合物； (b) caspase-3和caspase-9的激活增加； (c) 增殖物激活受体γ的表达增加。本研究显着扩展了我们对塞来昔布诱导抑制肝细胞癌细胞生长的作用和机制的认识。
Purpose: Cyclooxygenase-2 (COX-2) inhibitors cause growth inhibition of human hepatocellular carcinoma cells but it remains unclear whether this is both COX-2 dependent and independent. The related mechanisms remain to be determined. The present study was aimed to determine the effect of celecoxib on growth of hepatocellular carcinoma cells and xenografts and the related mechanisms.Experimental Design: Both low COX-2 expressing PLC/PRF/5 and high COX-2 expressing HuH7 cells, and nude mice bearing hepatocellular carcinoma xenografts were used to study the effect and mechanisms of celecoxib on hepatocellular carcinoma cell growth.Results: Celecoxib resulted in a comparable growth inhibition of both hepatocellular carcinoma cells that was associated with decreased production of prostaglandin E-2 and increased peroxisome proliferator-activated receptor gamma in both cells. Addition of prostaglandin E2 only partially counteracted the effect of celecoxib on both cells. Celecoxib resulted in a significant reduction of retinoblastoma phosphorylation and DP1/E2F1 complex in both cells. Celecoxib caused a significant increase of apoptosis and activation of caspase-3 and caspase-9 in both cells. In nude mice inoculated with HuH7 cells, celecoxib resulted in decreased frequency and mean weight of hepatocellular carcinoma xenografts.Conclusion: The present study showed that celecoxib causes COX-2-dependent and COX-2-independent growth inhibition of hepatocellular carcinoma cells and xenografts by (a) decreased retinoblastoma phosphorylation and DP1/E2F1 complex; (b) increased activation of caspase-3 and caspase-9; and (c) increased expression of proliferator-activated receptor gamma. The present study significantly extended our knowledge on the effect and mechanisms of celecoxib-induced inhibition of hepatocellular carcinoma cell growth.