Growth inhibition by the farnesyltransferase inhibitor FTI-277 involves Bcl-2 expression and defective association with Raf-1 in liver cancer cell lines.
Growth inhibition by the farnesyltransferase inhibitor FTI-277 involves Bcl-2 expression and defective association with Raf-1 in liver cancer cell lines.
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法尼基转移酶抑制剂 FTI-277 的生长抑制涉及肝癌细胞系中 Bcl-2 的表达以及与 Raf-1 的缺陷关联。
DOI：
10.1124/mol.63.1.159
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发表时间：
2003
影响因子：
3.6
通讯作者：
V. Carloni
中科院分区：
文献类型：
--
作者：
A. Mazzocca;S. Giusti;A. Hamilton;S. Sebti;P. Pantaleo;V. Carloni
法尼基转移酶抑制剂(FTI)在体内外阻断肿瘤细胞的生长，对正常细胞的毒性最小。一般来说，抑制蛋白质法尼化会导致G0/G1期细胞周期停滞，G2/M期细胞周期停滞，或者对细胞周期进程没有影响。FTI生物学的一个鲜为人知的方面是，这些药物诱导癌细胞生长停滞在细胞周期的G2/M期的能力。在本研究中，我们研究了法尼基转移酶抑制剂FTI-277对两种人肝癌细胞株HepG2和HuH7的影响。用FTI-277处理这些细胞可抑制RAS法尼化，并呈剂量依赖关系。FTI-277对HepG2和Huh7细胞生长均有抑制作用，细胞聚集于G2/M期。在HepG2和Huh7细胞中，FTI-277诱导细胞周期蛋白依赖性激酶抑制因子p27(Kip1)表达上调，而不影响细胞内P53和p21(Waf1)的表达水平。这一事件与细胞周期蛋白依赖性激酶2和细胞周期蛋白依赖性激酶1活性降低有关。此外，经FTI-277处理的HepG2和Huh7细胞中，Bcl2蛋白的表达增加，这与Raf-1和Bcl2的相关性降低是一致的。最后，瞬时转染显性负性RAS等位基因可诱导Bcl2的表达，并降低Bcl2/Raf-1的相关性，表明RAS是必需的。综上所述，这些发现表明p27(Kip1)和Bcl2的表达增加伴随着Ras、Raf-1和Bcl2之间的关联改变，提示这是FTI-277的生长抑制特性的原因。
Farnesyltransferase inhibitors (FTIs) block the growth of tumor cells in vitro and in vivo with minimal toxicity toward normal cells. In general, inhibition of protein farnesylation results in G0/G1 cell cycle block, G2/M cell cycle arrest, or has no effect on cell cycle progression. One aspect of FTI biology that is poorly understood is the ability of these drugs to induce cancer cell growth arrest at the G2/M phase of cell cycle. In the present study, we investigated the effects of the farnesyltransferase inhibitor FTI-277 on two human liver cancer cell lines, HepG2 and Huh7. Treatment of these cells with FTI-277 inhibited Ras farnesylation in a dose-dependent manner. Both HepG2 and Huh7 cell growth was inhibited by FTI-277 and cells accumulated at the G2/M phase of the cell cycle. In HepG2 and Huh7 cells, FTI-277 induced an up-regulation of the cyclin-dependent kinase inhibitor p27(Kip1) without affecting the cellular levels of p53 and p21(Waf1). This event correlated with reduced activity of the cyclin-dependent kinase 2 and cyclin-dependent kinase 1. Moreover, increased expression of Bcl-2 protein was observed in HepG2 and Huh7 cells treated with FTI-277, and this was coincidental with reduced association between Raf-1 and Bcl-2. Finally, transient transfection of a dominant-negative Ras allele induced Bcl-2 expression and reduced Bcl-2/Raf-1 association demonstrating a requirement for Ras. Taken together, these findings show that increased expression of p27(Kip1) and Bcl-2 is concomitant with altered association between Ras, Raf-1 and Bcl-2 and suggest that this is responsible for the growth-inhibitory properties of FTI-277.
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影响因子：
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作者：
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