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Analysis on the mechanism of growth inhibition by vitamin K2 in hepatoma cells

维生素K2抑制肝癌细胞生长的机制分析

基本信息

批准号：
16590606
负责人：
MIZUTA Toshihiko
金额：
$ 1.66万
依托单位：
Saga University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590606/
关键词：
vitamin K2 hepatoma cells 5-FU cyclin D1 matrix metalloproteinase Cvclin D1 増殖抑制効果転写因子NF-kB CDK inhibitor

项目摘要

(Purpose) To elucidate the mechanism of growth inhibition by vitamin K2 in hepatoma cells, we examined how apoptosis- and cell cycle-related factors were influenced by vitamin K2.(Methods) Using human hepatoma cell lines, HepG2, Hep 3B and Huh7, we tested about 1)induction of apoptosis and cell proliferation, 2)cell cycle, 3)expression of cyclin dependent kinase (CDK) inhibitors (p16, p21, p27), 4)expression of cyclin D1, 5)activation of cyclin D1 promoter, 6)binding activity of transcription factors (AP-1, NF-κB) to cyclin D1 promoter, 7)additive effect of anti-cancer agents (CDDP, 5-FU, VP-16, Docetaxel), 8)expression of matrix metalloproteinase (MMP-1, MMP-3, MMP-7), by addition of vitamin K2.(Results) 1)Vitamin K2 suppressed cell growth, but could not induce apoptosis, 2)vitamin K2 induced G1 arrest, 3)vitamin K2 increase the expression of CDK inhibitors, 4)vitamin K2 decrease the expression of cyclin D1, 5)vitamin K2 decrease promoter activity of cyclin D1, 6)vitamin K2 decrease binding activity of AP-1 and NF-κB to promoter region of cyclin D1, 7)vitamin K2 counteracts the action of CDDP, but enhances the suppressive effect on cell growth of 5-FU, VP-16 and Docetaxel, 8)vitamin K2 inhibits the expression of MMP-1, MMP-3 and MMP-7.(Conclusion) Vitamin K2 can induce G1 arrest in hepatoma cells by suppression of cyclin D1 expression through inhibition of transcription factor, NF-κB binding to cyclinD1 promoter as well as enhancement of CDK inhibitors expression. Furthermore, these results suggest the possibility on clinical application of vitamin K2 in the field of concomitant treatment with anti-cancer agents and suppression of tumor invasion.

(目的) 为了阐明维生素 K2 抑制肝癌细胞生长的机制，我们研究了维生素 K2 对细胞凋亡和细胞周期相关因子的影响。(方法) 使用人肝癌细胞系 HepG2、Hep 3B 和 Huh7，我们测试了 1) 诱导细胞凋亡和细胞增殖，2) 细胞周期，3) 细胞周期蛋白依赖性激酶的表达 (CDK)抑制剂(p16、p21、p27)、4)细胞周期蛋白D1的表达、5)细胞周期蛋白D1启动子的激活、6)转录因子(AP-1、NF-κB)与细胞周期蛋白D1启动子的结合活性、7)抗癌剂(CDDP、5-FU、VP-16、多西紫杉醇)的累加作用、8)基质的表达金属蛋白酶（MMP-1，MMP-3，MMP-7），通过添加维生素K2。（结果）1）维生素K2抑制细胞生长，但不能诱导细胞凋亡，2）维生素K2诱导G1阻滞，3）维生素K2增加CDK抑制剂的表达，4）维生素K2减少细胞周期蛋白D1的表达，5）维生素K2减少 cyclin D1启动子活性，6)维生素K2降低AP-1和NF-κB与cyclin D1启动子区的结合活性，7)维生素K2抵消CDDP的作用，但增强5-FU、VP-16和多西紫杉醇对细胞生长的抑制作用，8)维生素K2抑制MMP-1、MMP-3和MMP-7的表达。(结论) 维生素 K2 可通过抑制转录因子、NF-κB 与细胞周期蛋白 D1 启动子的结合以及增强 CDK 抑制剂的表达来抑制细胞周期蛋白 D1 的表达，从而诱导肝癌细胞 G1 期阻滞。此外，这些结果表明维生素K2在抗癌药物联合治疗和抑制肿瘤侵袭领域的临床应用的可能性。