Lebowitz P F, Sakamuro D, Prendergast G C
The Wistar Institute, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Cancer Res. 1997 Feb 15;57(4):708-13.
Farnesyl transferase inhibitors (FTIs) are a novel class of antitumor drugs that block the oncogenic activity of Ras. Because FTIs lack significant cell toxicity in vitro and in vivo, a significant question is how they cause tumor regression. We now report that FTIs are in fact potent activators of apoptosis in Ras-transformed cells if attachment to substratum is prevented. When cultured at high density or on polyHEMA, a nonadherent substrate, Ras-transformed cells exhibited massive DNA degradation and cell death within 24 h of treatment with the FTI L-739,749. Death was p53-independent and was inhibited by the apoptosis suppressor BCL-XL. Furthermore, apoptosis was significantly attenuated by ectopic expression of a farnesyl-independent form of RhoB, a Rho protein previously implicated as a critical target for inhibition by FTIs. The findings suggest a link between FTIs and Rho-dependent adhesion signaling. Furthermore, our work indicates that FTIs revert cells to a state in which cell-substratum attachment is necessary for viability and suggests that apoptosis forms the basis for drug-induced tumor regression.
法尼基转移酶抑制剂（FTIs）是一类新型的抗肿瘤药物，可阻断Ras的致癌活性。由于FTIs在体外和体内缺乏显著的细胞毒性，一个重要的问题是它们如何导致肿瘤消退。我们现在报告，在阻止与基质附着的情况下，FTIs实际上是Ras转化细胞中凋亡的有效激活剂。当在高密度条件下培养或在聚甲基丙烯酸羟乙酯（一种非粘附性底物）上培养时，Ras转化细胞在用FTI L-739,749处理后24小时内出现大量DNA降解和细胞死亡。死亡不依赖p53，并被凋亡抑制因子BCL-XL抑制。此外，通过异位表达一种不依赖法尼基化的RhoB形式，凋亡显著减弱，RhoB是一种Rho蛋白，之前被认为是FTIs抑制的关键靶点。这些发现表明FTIs与Rho依赖性粘附信号之间存在联系。此外，我们的研究表明，FTIs使细胞恢复到一种状态，在这种状态下细胞与基质的附着对生存能力至关重要，并表明凋亡是药物诱导肿瘤消退的基础。
