Anti-gastric cancer effects of celecoxib, a selective COX-2 inhibitor, through inhibition of Akt signaling
Anti-gastric cancer effects of celecoxib, a selective COX-2 inhibitor, through inhibition of Akt signaling
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DOI：
10.1111/j.1440-1746.2008.05599.x
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发表时间：
2009-03-01
影响因子：
4.1
通讯作者：
Song, In Sung
中科院分区：
文献类型：
--
作者：
Kim, Nayoung;Kim, Chung Hyun;Song, In Sung
以前，我们发现塞来昔布治疗可以显著减少胃癌细胞的存活数量，并且具有剂量和时间依赖性。然而，塞来昔布对胃癌细胞的具体抗癌作用尚未明确。本体外研究旨在研究塞来昔布抗胃癌作用的机制。3-处理AGS细胞后，进行（4，5-二甲基-2-噻唑基）-2，5-二苯基-2H-溴化四氮唑（MTT）测定（人胃癌细胞系，ATCC CRL 1739）与塞来昔布或吲哚美辛，并评价前列腺素E-2或LY 294002（PI 3 K抑制剂）的作用。tAkt的蛋白质印迹分析（总Akt），pAkt（磷酸化Akt），pGSK 3 β（磷酸化糖原合成酶激酶-3 β），pFKHR（磷酸化叉头转录因子）和caspase-9在各种浓度下进行（0，5，10，25，或50 μ mol/L）的塞来昔布或吲哚美辛处理AGS细胞24或48 h。PGE（2）（25或50 μ mol/L）可使AGS细胞的上述降低略有恢复。塞来昔布处理后AGS细胞pAkt表达降低，tAkt表达无明显变化，且呈剂量依赖性（P < 0.05）。在塞来昔布处理的AGS细胞中，pGSK 3 β和pFKHR的表达也显著降低。在塞来昔布治疗组中，Procaspase 9（47 kDa）经常被切割成37、35和17 kDa的片段。塞来昔布对胃癌细胞的作用可能是通过下调Akt、GSK 3 β、FKHR和上调caspase-9等线粒体凋亡途径来实现的。
Previously, we showed that treatment with celecoxib significantly reduced the number of viable gastric cancer cells, in a dose- and time-dependent manner. However, the specific anti-cancer effects of celecoxib on gastric cancer cells have not been clarified. The present in vitro study was carried out to investigate the mechanism involved in the anti-gastric cancer effects of celecoxib.3-(4,5-Dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was carried out after treating AGS cells (human gastric cancer cell line, ATCC CRL 1739) with celecoxib or indomethacin, and the effect of prostaglandin E-2 or LY294002 (PI3K inhibitor) was evaluated. Western blot analysis of tAkt (total Akt), pAkt (phosphorylated Akt), pGSK3 beta (phosphorylated glycogen synthase kinase-3 beta), pFKHR (phosphorylated forkhead transcriptional factor), and caspase-9 was carried out at various concentrations (0, 5, 10, 25, or 50 mu mol/L) of celecoxib or indomethacin-treatment for 24 or 48 h in AGS cells.Celecoxib- or LY294002-induced cell death was found to occur in a dose-dependent manner in AGS cells, and these decreases were slightly recovered by the addition of PGE(2) (25 or 50 mu mol/L). The expression of pAkt but not tAkt was lower in the celecoxib treated-AGS cells and the response was dose dependent (P < 0.05). The expression of pGSK3 beta and pFKHR was also significantly decreased in the celecoxib treated-AGS cells. Procaspase 9 (47 kDa) was frequently cleaved into 37, 35 and 17 kDa fragments in the celecoxib-treatment group. However, these changes in cell signal transduction were not observed in the indomethacin treated-AGS cells.The anti-cancer effects of celecoxib on gastric cancer cells might be partly mediated by downregulation of Akt, GSK3 beta, FKHR, and upregulation of caspase-9, in the mitochondrial apoptotic pathway.