A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines.
A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines.
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发表时间：
1995-11
期刊：
影响因子：
11.2
通讯作者：
L. Sepp-Lorenzino;Zhenping Ma;E. Rands;N. Kohl;J. Gibbs;A. Oliff;N. Rosen
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文献类型：
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作者：
L. Sepp-Lorenzino;Zhenping Ma;E. Rands;N. Kohl;J. Gibbs;A. Oliff;N. Rosen
法尼基蛋白转移酶（FPTase）催化一系列Ras翻译后修饰的第一步，这些修饰是完全生物活性所必需的。已经设计了FPTase的拟肽抑制剂，可以在体内和体外选择性地阻断法尼化。这些抑制剂阻止Ras加工和膜定位，并有效逆转Rat1-v-ras细胞的转化表型，但对v-raf或v-mos转化的细胞无效。我们测试了FPTase抑制剂L-744,832 （FTI）对人肿瘤细胞系锚定依赖性和非依赖性生长的影响。2-20微米的FTI可抑制70%以上的肿瘤细胞系的生长，而非转化上皮细胞的锚定依赖性生长对该化合物的影响不太敏感。对药物的反应与肿瘤细胞的起源或是否含有突变激活的ras之间没有相关性。事实上，具有野生型ras和活性蛋白酪氨酸激酶（其转化表型可能依赖于ras途径的上游激活）的细胞系对该药物特别敏感。为明确FTI作用的重要靶点，探讨了FTI的细胞耐药机制。这不是药物积累改变或FPTase不敏感的功能，因为在所有测试的细胞系中，用抑制剂治疗1小时内，FPTase活性很容易被抑制。此外，在敏感细胞和耐药细胞中，抑制细胞蛋白法尼化和特异性抑制层粘连蛋白B加工的一般模式是相同的。此外，Ras的功能激活在敏感和抗性细胞系中均受到相同程度的抑制。然而，在敏感细胞中，FTI抑制表皮生长因子诱导的丝裂原活化蛋白激酶的激活，而在两种抗性细胞系中则没有。这些数据表明，该药物确实抑制ras功能，并且某些细胞中的耐药性与酪氨酸激酶激活丝裂原激活蛋白激酶的ras独立途径的存在有关。我们得出结论，FPTase抑制剂是一种有效的抗肿瘤药物，对许多类型的人类癌细胞系具有活性，包括那些野生型ras。
Farnesyl protein transferase (FPTase) catalyzes the first of a series of posttranslational modifications of Ras required for full biological activity. Peptidomimetic inhibitors of FPTase have been designed that selectively block farnesylation in vivo and in vitro. These inhibitors prevent Ras processing and membrane localization and are effective in reversing the transformed phenotype of Rat1-v-ras cells but not that of cells transformed by v-raf or v-mos. We have tested the effect of the FPTase inhibitor L-744,832 (FTI) on the anchorage-dependent and -independent growth of human tumor cell lines. The growth of over 70% of all tumor cell lines tested was inhibited by 2-20 microM of the FTI, whereas the anchorage-dependent growth of nontransformed epithelial cells was less sensitive to the effects of the compound. No correlation was observed between response to drug and the origin of the tumor cell or whether it contained mutationally activated ras. In fact, cell lines with wild-type ras and active protein tyrosine kinases in which the transformed phenotype may depend on upstream activation of the ras pathway were especially sensitive to the drug. To define the important targets of FTI action, the mechanism of cellular drug resistance was examined. It was not a function of altered drug accumulation or of FPTase insensitivity since, in all cell lines tested, FPTase activity was readily inhibited within 1 h of treatment with the inhibitor. Furthermore, the general pattern of inhibition of cellular protein farnesylation and the specific inhibition of lamin B processing were the same in sensitive and resistant cells. In addition, functional activation of Ras was inhibited to the same degree in sensitive and resistant cell lines. However, the FTI inhibited the epidermal growth factor-induced activation of mitogen-activated protein kinases in sensitive cells but not in two resistant cell lines. These data suggest that the drug does inhibit ras function and that resistance in some cells is associated with the presence of Ras-independent pathways for mitogen-activated protein kinase activation by tyrosine kinases. We conclude that FPTase inhibitors are potent antitumor agents with activity against many types of human cancer cell lines, including those with wild-type ras.