The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells
The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells
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DOI：
10.1074/jbc.m006213200
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发表时间：
2001-05-11
影响因子：
4.8
通讯作者：
Sebti, SM
中科院分区：
文献类型：
--
作者：
Crespo, NC;Ohkanda, J;Sebti, SM
尽管法尼基转移酶抑制剂（FTIs）是目前在临床试验中的一类新型治疗剂，具有临床前突出的抗癌活性和令人印象深刻的无毒性，但其作用机制尚不清楚。为了增强我们对FTIs如何抑制肿瘤生长的理解，我们研究了它们对两种人肺癌细胞系A-549和Calu-1的细胞周期进展的影响。在本报告中，我们在同步化的A-549和Calu-1细胞中显示，FTI-2153处理导致细胞分裂周期有丝分裂期的细胞大量积累，一些细胞处于G（0）/G（1）期。此外，微管免疫染色和4，6-二脒基-2-苯基吲哚DNA染色表明，FTI-2153诱导的有丝分裂中的蓄积是由于这些细胞无法从前期进展到中期。FTI-2153抑制A-549和Calu-1细胞形成双极纺锤体的能力，并引起单腹纺锤体的形成。此外，FTI-2153诱导了环状染色体形态并抑制了染色体排列。延时视频显微镜证实了这一结果，显示FTI-2153处理的细胞无法在中期平板上对齐其染色体。FTI-2153不影响两种法尼基化着丝粒蛋白CENP-E和CENP-F在着丝粒上的定位。因此，FTI通过有丝分裂和肿瘤生长抑制进展的机制是通过阻断双极纺锤体形成和染色体排列。
Even though farnesyltransferase inhibitors (FTIs), a novel class of therapeutic agents presently in clinical trials, have preclinically outstanding anticancer activity and impressive lack of toxicity, their mechanism of action is not well understood. To enhance our understanding of how FTIs inhibit the growth of tumors, we have investigated their effects on eel cycle progression of two human lung cancer cell lines, A-549 and Calu-1. In this report, we show in synchronized A-549 and Calu-1 cells that FTI-2153 treatment resulted in a large accumulation of cells in the mitosis phase of the cell division cycle, with some cells in the G(0)/G(1) phase. Furthermore, microtubule immunostaining and 4,6-diamidino-2-phenylindole DNA staining demonstrated that the FTI-2153-induced accumulation in mitosis is due to the inability of these cells to progress from prophase to metaphase. FTI-2153 inhibited the ability of A-549 and Calu-1 cells to form bipolar spindles and caused formation of monoasteral spindles. Furthermore, FTI-2153 induced a ring-shaped chromosome morphology and inhibited chromosome alignment. Time-lapse videomicroscopy confirmed this result by showing that FTI-2153-treated cells are unable to align their chromosomes at the metaphase plate. FTI-2153 did not affect the localization to the kinetochores of two farnesylated centromeric proteins, CENP-E and CENP-F. Thus, a mechanism by which FTIs inhibit progression through mitosis and tumor growth is by blocking bipolar spindle formation and chromosome alignment.