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首页> 外文期刊>Anticancer Research: International Journal of Cancer Research and Treatment >Inhibition of farnesyl-protein-transferase in neuroblastoma cells by alpha-hydroxyfarnesylphosphonate.
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Inhibition of farnesyl-protein-transferase in neuroblastoma cells by alpha-hydroxyfarnesylphosphonate.

机译：α-羟基法呢基膦酸酯抑制神经母细胞瘤细胞中的法呢基蛋白转移酶。

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摘要

Oncogenic Ras is responsible for malignant transformation in a variety of tumors. Farnesylation of Ras by farnesyl-protein-transferase (FPTase) is necessary for membrane localization of Ras-proteins, a prerequisite for its biological activity. Although mutations in ras genes are rare in neuroblastoma inactivation of Ras by inhibition of the FPTase is of interest in neuroblastoma. In this tumor, amplification of N-myc is frequently observed and expression of N-myc is induced via Ras signaling. Farnesyl-protein-transferase of neuroblastoma cells is inhibited by alpha-hydroxyfarnesylphosphonate. In homogenates of the cell line SK-N-AS an ID50 = 6.5 microM is estimated, in SK-N-SH the ID50 is 3.4 microM. The consequences of the inhibition of FPTase on the membrane localization was examined by immunoblots. Western blots of membrane proteins analysed with H-ras and N-ras specific antibodies revealed that H-ras protein is more sensitive to the inhibition of FPTase than N-ras protein. After culturing neuroblastoma cells for 24 hrs in the presence of 20 microM alpha-hydroxyfarnesylphosphonate H-ras protein completely dissappeared from the membrane fraction whereas N-ras protein was only affected by 50%. K-ras was not detectable on Western blots of three neuroblastoma cell lines. The experiments showed that FPTase inhibitors are effective in neuroblastoma cells but for complete inactivation of N-ras stronger conditions are required than for H-ras.
机译：致癌性Ras负责多种肿瘤的恶性转化。法呢基蛋白转移酶（FPTase）对法呢基的法呢基化是Ras蛋白膜定位的必要条件，这是其生物学活性的前提。尽管ras基因突变在神经母细胞瘤中很少见，但通过抑制FPTase使Ras失活是神经母细胞瘤中令人关注的问题。在该肿瘤中，经常观察到N-myc的扩增，并且通过Ras信号传导诱导N-myc的表达。 α-羟基法呢基膦酸酯抑制神经母细胞瘤细胞的法呢基蛋白转移酶。在细胞系SK-N-AS的匀浆中，估计ID50 = 6.5 microM，在SK-N-SH中ID50为3.4 microM。通过免疫印迹检查了FPTase抑制对膜定位的影响。用H-ras和N-ras特异性抗体分析的膜蛋白的蛋白质印迹表明，H-ras蛋白对FPTase的抑制作用比N-ras蛋白更敏感。在存在20 microMα-羟基法呢基膦酸酯的情况下培养神经母细胞瘤细胞24小时后，H-ras蛋白从膜部分完全消失，而N-ras蛋白仅受到50％的影响。在三种神经母细胞瘤细胞系的蛋白质印迹中无法检测到K-ras。实验表明FPTase抑制剂在神经母细胞瘤细胞中有效，但要使N-ras完全失活，需要比H-ras更强的条件。

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