γ-secretase inhibitors exerts antitumor activity via down-regulation of Notch and Nuclear factor kappa B in human tongue carcinoma cells
γ-secretase inhibitors exerts antitumor activity via down-regulation of Notch and Nuclear factor kappa B in human tongue carcinoma cells
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DOI：
10.1111/j.1601-0825.2006.01334.x
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发表时间：
2007-11-01
期刊：
影响因子：
3.8
通讯作者：
Wu, X.
中科院分区：
文献类型：
--
作者：
Yao, J.;Duan, L.;Wu, X.
目的研究γ-分泌酶抑制剂（GSIs）对人舌癌细胞生长的影响，为GSIs治疗舌癌提供分子机制。通过甲基噻唑四唑方法测定细胞生长。流式细胞术和/或共聚焦显微镜分析细胞周期和凋亡。RT-PCR和Western blot检测细胞内的表达水平。结果L-685，458剂量依赖性地抑制人舌癌Tca 8113细胞的生长，使细胞周期阻滞于G 0-G1期，并诱导细胞凋亡。L-685，458剂量依赖性地降低了Hairy/Split-1增强子（Notch激活的靶点）的mRNA和蛋白水平。此外，L-685，458下调细胞周期蛋白D1、B细胞淋巴细胞白血病原癌基因2和c-Myc的表达，这些表达由转录因子NF-κ B调节。结论GSI L-685，458对人舌癌有一定的治疗价值。L-685，458的抑瘤作用可能部分通过调节Notch和NF-κ B发挥作用。
Objective To investigate the effect of the gamma-secretase inhibitors (GSIs) on the growth of human tongue carcinoma cells and to provide the molecular mechanism for potential application of GSIs in the treatment of tongue carcinoma.Materials and Methods Human tongue carcinoma Tca8113 cells were cultured with the GSI L-685 458. Cell growth was determined by the methylthiazole tetrazolium method. Cell cycle and apoptosis were analyzed by flow cytometry and/or confocal microscopy. RT-PCR and Western blot were employed to determine the intracellular expression levels. Nuclear factor kappa B (NF-kappa B) activation was examined by electrophoretic mobility shift assay.Results L-685,458 dose-dependently inhibited the growth of human tongue carcinoma Tca8113 cells by inducing G0-G1 cell cycle arrest and apoptosis. The mRNA and protein levels of Hairy/Enhancer of Split-1, a target of Notch activation, were decreased dose-dependently by L-685,458. Furthermore, L-685,458 down-regulated cyclin D1, B-cell lymphocytic-leukemia proto-oncogene 2 and c-Myc expressions, which are regulated by the transcription factor NF-kappa B. Coincident with this observation, L-685,458 induced a dose-dependent reduction of constitutive NF-kappa B activation in Tca8113 cells.Conclusions The GSI L-685,458 may have a therapeutic value for the treatment of human tongue carcinoma. Moreover, the effects of L-685,458 in tumor inhibition may act partially via the modulation of Notch and NF-kappa B.