The Ras inhibitor farnesylthiosalicylic acid as a potential therapy for neurofibromatosis type 1
The Ras inhibitor farnesylthiosalicylic acid as a potential therapy for neurofibromatosis type 1
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DOI：
10.1158/1078-0432.ccr-06-0792
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发表时间：
2006-09-15
影响因子：
11.5
通讯作者：
Kloog, Yoel
中科院分区：
文献类型：
--
作者：
Barkan, Batya;Starinsky, Sigal;Kloog, Yoel
目的：法尼基硫代水杨酸（FTS）是一种Ras抑制剂，可将所有活性Ras亚型从膜上清除。我们评估了FTS逆转恶性周围神经鞘肿瘤（MPNST） 1型神经纤维瘤病（NF1）相关肿瘤细胞系转化表型的能力。实验设计：对nf1突变进行基因分型，分析等位基因丢失，并测定MPNST细胞系ST88-14、S265P21和90-8中神经纤维蛋白的表达水平。评估FTS对gtp结合Ras （Ras- gtp）及其主要下游靶点的影响，以及对小鼠细胞形态、锚定依赖性和非锚定依赖性生长和肿瘤生长的影响。结果：MPNST细胞系为双等位基因，NF1失活，神经纤维蛋白缺乏。我们发现，在所有NF1缺陷的MPNST细胞系（NF1细胞）中，FTS治疗缩短了相对较长的Ras激活和向细胞外信号调节激酶、Akt和RaIA信号传导的持续时间。与非nf1正常表达神经纤维蛋白的MPNST细胞系中观察到的相似。FTS的这些作用导致Ras-GTP及其激活靶标的稳态水平降低。FTS对锚定依赖性和非锚定依赖性NF1细胞的生长均有剂量依赖性抑制，且抑制作用与Ras-GTP水平呈正相关。NF1细胞被发现具有强肌动蛋白应激纤维，这种表型也被FTS纠正。口服FTS可抑制裸鼠NF1肿瘤的生长。结论：FTS处理NF1细胞使Ras-GTP水平正常化，导致转化表型逆转，抑制肿瘤生长。因此，FTS可能被认为是治疗NF1的潜在药物。
Purpose: Farnesylthiosalicylic acid (FTS) is a Ras inhibitor that dislodges all active Ras isoforms from the membrane. We assessed the ability of FTS to reverse the transformed phenotype of neurofibromatosis type 1 (NF1) -associated tumor cell lines of malignant peripheral nerve sheath tumor (MPNST).Experimental Design: nf1 mutations were genotyped, allelic losses were analyzed, and neurofibromin expression levels were determined in MPNST cell lines ST88-14, S265P21, and 90-8. The effects of FTS on GTP-bound Ras (Ras-GTP) and its prominent downstream targets, as well as on cell morphology, anchorage-dependent and anchorage-independent growth, and tumor growth in mice, were assessed.Results: The MPNST cell lines were biallelic, NF1 inactive, and neurofibromin deficient. We show that FTS treatment shortened the relatively long duration of Ras activation and signaling to extracellular signal-regulated kinase, Akt, and RaIA in all NF1-deficient MPNST cell lines (NF1 cells). to that observed in a non-NF1, normally expressing neurofibromin MPNST cell line. These effects of FTS led to lower steady-state levels of Ras-GTP and its activated targets. Both anchorage-dependent and anchorage-independent growth of NF1 cells were dose dependently inhibited by FTS, and the inhibition correlated positively with Ras-GTP levels. NF1 cells were found to possess strong actin stress fibers, and this phenotype was also corrected by FTS. NF1 tumor growth in a nude mouse model was inhibited by oral FTS.Conclusions: FTS treatment of NF1 cells normalized Ras-GTP levels, resulting in reversal of the transformed phenotype and inhibition of tumor growth. FTS may therefore be considered as a potential drug for the treatment of NF1.