R-Etodolac decreases β-catenin levels along with survival and proliferation of hepatoma cells
R-Etodolac decreases β-catenin levels along with survival and proliferation of hepatoma cells
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DOI：
10.1016/j.jhep.2006.11.017
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发表时间：
2007-05-01
影响因子：
25.7
通讯作者：
Monga, Satdarshan P. S.
中科院分区：
文献类型：
--
作者：
Behari, Jaideep;Zeng, Gang;Monga, Satdarshan P. S.
背景/目的：环氧化酶（考克斯）-2依赖性和非依赖性抑制肝癌细胞的机制已被证实。在这里，我们研究了塞来昔布（一种考克斯-2-抑制剂）和R-依托度酸（一种非甾体抗炎药依托度酸的对映体，缺乏COX抑制活性）对Wnt/β-连环蛋白通路和人肝癌细胞的影响。方法：用塞来昔布或R-依托度酸处理Hep 3B和HepG 2细胞系，并检查活力、DNA合成、Wnt/β-连环蛋白途径组分，结果：高剂量塞来昔布通过诱导β-catenin蛋白通过GSK 3 β和APC的降解而影响β-catenin蛋白，同时沿着肿瘤细胞增殖和存活的减少。生理剂量的R-依托度酸导致总β-连环蛋白和活化β-连环蛋白蛋白减少，继发于其基因表达减少，并通过GSK 3 β活化进行后处理。此外，在膜上也观察到β-连环蛋白-E-钙粘蛋白增加。β-连环蛋白依赖性Tcf报告基因活性的相关抑制、下游靶基因产物谷氨酰胺合成酶和细胞周期蛋白DI的水平降低以及肝癌细胞增殖和存活的降低是明显的。塞来昔布的抗肿瘤作用（高浓度）和R-依托度酸（生理剂量）对HCC细胞的作用伴随着β-连环蛋白的下调，证明了在肝细胞癌中的有用的治疗策略。(C)2007年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: Inhibition of hepatoma cells by cyclooxygenase (COX)-2-dependent and -independent mechanisms has been shown previously. Here, we examine the effect of Celecoxib, a COX-2-inhibitor and R-Etodolac, an enantiomer of the nonsteroidal anti-inflammatory drug Etodolac, which lacks COX-inhibitory activity, on the Wnt/beta-catenin pathway and human hepatoma cells.Methods: Hep3B and HepG2 cell lines were treated with Celecoxib or R-Etodolac, and examined for viability, DNA synthesis, Wnt/beta-catenin pathway components, and downstream target gene expression.Results: Celecoxib at high doses affected beta-catenin protein by inducing its degradation via GSK3 beta and APC along with diminished tumor cell proliferation and survival. R-Etodolac at physiological doses caused decrease in total and activated beta-catenin protein secondary to decrease in its gene expression and post-translationally through GSK3 beta activation. In addition, increased beta-catenin-E-cadherin was also observed at the membrane. An associated inhibition of beta-catenin-dependent Tcf reporter activity, decreased levels of downstream target gene products glutamine synthetase and cyclin-DI, and decreased proliferation and survival of hepatoma cells was evident.Conclusions: The antitumor effects of Celecoxib (at high concentrations) and R-Etodolac (at physiological doses) on HCC cells were accompanied by the down-regulation of beta-catenin demonstrating a useful therapeutic strategy in hepatocellular cancer. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.