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作 者:赵名[1] 王生余[1] 候春梅[1] 杜芝燕[1] 徐元基[1] 于晓妉[1]
机构地区:[1]军事医学科学院基础医学研究所,北京100850
出 处:《中国肿瘤生物治疗杂志》2006年第2期83-87,共5页Chinese Journal of Cancer Biotherapy
基 金:国家自然科学基金重点项目资助课题(30330620)
摘 要:目的:研究组蛋白去乙酰化酶(HDAC)抑制剂FK228诱导前列腺癌细胞系DU145凋亡的作用机制。方法:MTT比色法测定FK228抑制DU145细胞增殖及其对细胞的杀伤效应;瑞氏-姬姆萨染色观察细胞形态的变化;流式细胞术分析细胞周期的改变;蛋白印迹实验检测细胞内蛋白表达水平的变化。结果:FK228明显抑制DU145细胞体外增殖,并介导细胞死亡;12.5 ng/ml FK228作用细胞48 h后,细胞存活率降至63.7%;伴有细胞形态改变及细胞周期阻滞于G_0/G_1期;细胞内多种重要的激酶蛋白,包括EGFR、Her2、RM-1、Sic、Cdk4、Akt及凋亡抑制蛋白Survivin均发生了不同程度的降解,细胞内两条重要的生存信号通路Raf-MEK-ERK及PI3K/Akt被阻断,细胞发生凋亡。结论:FK228可以通过清除细胞内重要信号蛋白、阻断细胞生存信号通路来诱导DU145细胞发生凋亡。Objective: To investigate the underlying mechanism of histone deacetylase (HDAC) inhibitor FK228-induced apoptosis of the prostate cancer cell line DU145. Methods: The inhibitory effect of FK228 on DU145 cell growth and its cytotoxicity were determined by MTT assay; cell cycle arrest was detected by flow cytometry assay; morphological change was observed by Giemsa staining; and defined kinase protein levels were determined by Western blot analysis. Resuits: FK228 obviously inhibited DU145 cells growth , arrested cell cycle at Go/G, phase, induced ceils morphological changes and degraded several kinase proteins, including EGFR, Her2, Raf-1, Src, Cdk4 and IAP member Survivin. The degradation of these kinases blocked Raf-Mek-Erk and PI3K/Akt survival signal pathways, inducing apoptosis. Conclusion: FK228 may induce DU145 cell apoptosis through depletion of multiple kinase proteins and blockade of survival signal pathways of DU145 cells.
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