Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells.
Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells.
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DOI：
10.1073/pnas.95.26.15356
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发表时间：
1998-12
影响因子：
11.1
通讯作者：
N. Suzuki;J. Urano;F. Tamanoi
中科院分区：
文献类型：
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作者：
N. Suzuki;J. Urano;F. Tamanoi
法尼基转移酶抑制剂（FTIs）代表一类新的抗癌药物，其在阻断肿瘤生长方面显示出希望。在这里，我们报告说，FTIs能够诱导细胞凋亡的转化，但不是未转化的细胞。用FTIs处理v-K-ras转化的正常大鼠肾（KNRK）细胞导致诱导凋亡细胞形态、染色质浓缩和DNA片段化。此外，荧光激活细胞分选仪分析的FTIR处理的KNRK细胞显示亚G1凋亡峰（染色体含量<2 N）。仅当细胞在低血清条件（0.1%胎牛血清）下生长时，这种FTI诱导的细胞凋亡才是明显的，并且在转化的KNRK细胞中选择性地观察到，而在未转化的NRK细胞中没有观察到。对这种凋亡机制的进一步分析表明，FTI处理KNRK细胞导致半胱天冬酶3的激活，但不激活半胱天冬酶1。此外，添加Z-DEVD-fetamine（一种干扰半胱天冬酶3活性的试剂）可以剂量依赖性方式抑制FTI诱导的细胞凋亡。将CASP-3基因导入缺乏半胱天冬酶3活性的MCF 7细胞中，导致FTI诱导的凋亡显著增加。此外，FTI诱导细胞色素c释放到胞质溶胶中。这种释放是半胱天冬酶3介导的细胞凋亡的重要特征。这些结果表明，FTIs通过从线粒体释放细胞色素c，导致半胱天冬酶3活化来诱导细胞凋亡。
Farnesyltransferase inhibitors (FTIs) represent a new class of anticancer drugs that show promise in blocking the growth of tumors. Here, we report that FTIs are capable of inducing apoptosis of transformed but not untransformed cells. Treatment of v-K-ras-transformed normal rat kidney (KNRK) cells with FTIs leads to the induction of apoptotic cell morphology, chromatin condensation and DNA fragmentation. In addition, fluorescence-activated cell sorter analysis of FTI-treated KNRK cells shows a sub-G1 apoptotic peak (chromosome content of <2 N). This FTI-induced apoptosis is evident only when the cells are grown in low serum conditions (0.1% fetal calf serum) and is observed selectively with transformed KNRK cells and not with untransformed NRK cells. Further analysis of the mechanism underlying this apoptosis has shown that FTI treatment of KNRK cells results in the activation of caspase 3 but not caspase 1. Moreover, the addition of Z-DEVD-fmk, an agent that interferes with caspase 3 activity, can inhibit FTI-induced apoptosis in a dose-dependent manner. Introduction of the CASP-3 gene into MCF7 cells, which lack caspase 3 activity, results in a significant increase of FTI-induced apoptosis. Furthermore, FTI induces the release of cytochrome c into the cytosol. This release is an important feature of caspase 3-mediated apoptosis. These results suggest that FTIs induce apoptosis through the release of cytochrome c from the mitochondria resulting in caspase 3 activation.