Cui Wei, Yu Chang-Hong, Hu Ke-Qin
Division of Gastroenterology and Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Orange, California 92868, USA.
Clin Cancer Res. 2005 Nov 15;11(22):8213-21. doi: 10.1158/1078-0432.CCR-05-1044.
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.
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.
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 E(2) 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.
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.
环氧化酶 -2（COX -2）抑制剂可抑制人肝癌细胞生长，但这种抑制是否依赖于COX -2以及是否存在非COX -2依赖机制尚不清楚，相关机制有待确定。本研究旨在确定塞来昔布对肝癌细胞及其异种移植瘤生长的影响及相关机制。
采用低COX -2表达的PLC/PRF/5细胞和高COX -2表达的HuH7细胞，以及接种了肝癌异种移植瘤的裸鼠，研究塞来昔布对肝癌细胞生长的影响及机制。
塞来昔布对两种肝癌细胞均产生了类似的生长抑制作用，这与细胞中前列腺素E2产量降低及过氧化物酶体增殖物激活受体γ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。塞来昔布使两种细胞中的视网膜母细胞瘤磷酸化及DP1/E2F1复合物显著减少。塞来昔布使两种细胞中的凋亡显著增加，并激活了caspase -3和caspase -9。在接种了HuH7细胞的裸鼠中，塞来昔布使肝癌异种移植瘤的发生率和平均重量降低。
本研究表明，塞来昔布通过以下方式对肝癌细胞及其异种移植瘤产生COX -2依赖和COX -2非依赖的生长抑制作用：（a）降低视网膜母细胞瘤磷酸化及DP1/E2F1复合物；（b）增加caspase -3和caspase -9的激活；（c）增加增殖物激活受体γ的表达。本研究显著扩展了我们对塞来昔布诱导肝癌细胞生长抑制的作用及机制的认识。
