ROLE OF RHO IN FARNESYLTRANSFERASE INHIBITOR RESPONSES

法尼基转移酶抑制剂（FTIs）是临床试验中首批旨在阻断癌细胞信号转导的“设计药物”之一。fti被用来攻击含有致癌Ras的肿瘤，Ras的功能依赖于翻译后的法尼化。临床前试验表明，FTIs对恶性转化细胞具有显著的特异性作用。然而，机制研究对Ras是否是药物抑制的必要靶点提出了质疑。因此，除Ras外，FTI靶蛋白的作用机制和特性已成为重要的问题。指导假设和具体目标。我们建议验证FTIs部分通过改变Rho戊酰化和功能起作用的假设（“FTI-Rho假设”）。初步研究提示RhoB作为一种研究范式。将研究与FTI反应和Rho改变相关的细胞粘附和基因激活事件。将定义fti区分细胞凋亡和细胞生长抑制的机制。简而言之，我们的目标是1)确定Rho作为FTI靶点，2)确定介导FTI反应所需的Rho依赖事件，3)确定决定生长抑制与凋亡的因素。创新与意义。在我们的提议中，创新的主要元素是将知识焦点从Ras转移到Rho，作为理解FTI在癌细胞中的作用机制的领域。确定FTI机制将促进临床应用以及对癌细胞病理生理学的新见解。

Farnesyltransferase inhibitors (FTIs) are among the first 'designer drugs' in clinical trials aimed at blocking cancer cell signal transduction. FTIs were made to attack tumors containing oncogenic Ras, whose function depends upon posttranslational farnesylation. Preclinical trials have demonstrated strikingly specific effects of FTIs against malignantly transformed cells. However, mechanistic investigations have raised doubts that Ras is a necessary target for drug inhibition. Thus, the mechanism of action and identity of FTI target proteins other than Ras have emerged as important questions. Guiding Hypothesis and Specific Aims. We propose to test the hypothesis that FTIs act in part through alteration of Rho prenylation and function (the 'FTI-Rho hypothesis'). Preliminary studies prompt RhoB as a paradigm for study. Cell adhesion and gene activation events related to FTI response and Rho alteration will be investigated. Mechanisms that distinguish apoptosis and cell growth inhibition by FTIs will be defined. In short, we aim to 1) establish Rho as an FTI target, 2) identify Rho-dependent events required to mediate FTI response, and 3) define the factors that dictate growth inhibition versus apoptosis. Innovation and Significance. The main element of innovation in our proposal is the shift of intellectual focus from Ras to Rho as a realm to understand the mechanism of FTI action in cancer cells. Defining FTI mechanism(s) will promote clinical applications as well as novel insights into cancer cell pathophysiology.