A chenodeoxycholic derivative, HS-1200, induces apoptosis and cell cycle modulation via Egr-1 gene expression control on human hepatoma cells
A chenodeoxycholic derivative, HS-1200, induces apoptosis and cell cycle modulation via Egr-1 gene expression control on human hepatoma cells
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DOI：
10.1016/j.canlet.2008.04.038
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发表时间：
2008-10-18
期刊：
影响因子：
9.7
通讯作者：
Kim, Nam Deuk
中科院分区：
文献类型：
--
作者：
Park, Sang Eun;Lee, Sun Wha;Kim, Nam Deuk
我们以前报道过，HS-1200，一种合成的鹅去氧胆酸衍生物，在各种人类癌细胞中具有诱导凋亡的活性。本研究旨在研究HS-1200是否对HepG 2（野生型p53）和Hep 3B（p53缺失）人肝癌细胞具有抗癌作用。通过MTT法、细胞核染色、DNA片段化和流式细胞术分析，HS-1200处理两种细胞导致生长抑制和诱导凋亡。凋亡的增加与Bcl-2/Bax蛋白表达比例的改变有关。此外，流式细胞仪分析表明，HS-1200诱导G1期阻滞在两个细胞。当分析细胞周期相关蛋白的表达时，我们发现HS-1200降低了细胞周期蛋白D1、细胞周期蛋白A和Cdk 2的表达水平。HS-1200处理还导致HepG 2细胞中p21（WAF 1/CIP 1）的表达水平以p53依赖的方式增加，而Hep 3B细胞中p21（WAF 1/CIP 1）的表达水平以p53非依赖的方式增加。此外，p27（KIP 1）的表达水平在两种细胞系中均增加。我们还观察到HS-1200降低了环氧合酶（考克斯）-2 mRNA和蛋白的表达水平。此外，HS-1200处理在早期时间点显著诱导Egr-1表达，并且HS-1200处理后增加的p53、p21（WAF 1/CIP 1）、p27（KIP 1）和考克斯-2表达水平在HepG 2细胞中被完全抑制，在Hep 3B细胞中被部分抑制，这是通过沉默Egr-1实现的。总之，这些研究结果提供了重要的新的见解，可能的分子机制的合成胆汁酸衍生物，HS-1200，通过Egr-1的调节抗癌活性。(c)2008爱思唯尔爱尔兰有限公司保留所有权利。
We previously reported that HS-1200, a synthetic chenodeoxycholic acid derivative, has apoptosis-inducing activity in various human cancer cells. The present study was undertaken to examine whether HS-1200 had an anticancer effect on HepG2 (wild-type p53) and Hep3B (p53 deleted) human hepatoma cells. Treatment of both cells with HS-1200 resulted in growth inhibition and induction of apoptosis as measured by MTT assay, nuclear staining, DNA fragmentation and flow cytometry analysis. The increase in apoptosis was associated with the alteration in the ratio of Bcl-2/Bax protein expression. In addition, flow cytometry analysis indicated that HS-1200 induced G1 phase arrest in both cells. When analyzing the expression of cell cycle-related proteins, we found that HS-1200 reduced the expression levels of cyclin D1, cyclin A, and Cdk2. HS-1200 treatment also caused an increase in the expression levels of p21(WAF1/CIP1) in HepG2 cells in a p53-dependent manner and in Hep3B cells in a p53-independent manner. Moreover, the expression level of p27(KIP1) was increased in both cell lines. We also observed that HS-1200 decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression. Furthermore, HS-1200 treatment markedly induced the Egr-1 expression at an early time point, and the increased expression levels of p53, p21(WAF1/CIP1), p27(KIP1), and COX-2 after treatment with HS-1200 were completely inhibited in HepG2 cells and partially inhibited in Hep3B cells by silencing of Egr-1, respectively. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anticancer activity of the synthetic bile acid derivative, HS-1200, through Egr-1 regulation. (c) 2008 Elsevier Ireland Ltd. All rights reserved.