Rheb GTPase as chemotherapeutic target for brain tumors

Rheb GTPase 作为脑肿瘤化疗靶点

• 批准号: 7052093
• 负责人: LAWRENCE A. QUILLIAM
• 金额: $ 23.13万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-11 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052093
• 关键词: alkyltransferase; antineoplastics; athymic mouse; brain neoplasms; cell growth regulation; cell line; enzyme activity; enzyme induction /repression; enzyme inhibitors; guanine nucleotide exchange factors; guanosinetriphosphatase activating protein; guanosinetriphosphatases; human tissue; neoplastic growth; phosphomonoesterases; prenylation

DESCRIPTION (provided by applicant): Loss of the PTEN tumor suppressor is frequently associated with the malignant progression of brain tumors. This lipid phosphatase plays a key role in regulating PI3K/Akt signaling which, through TSC2, activates the mTOR/S6K pathway. We recently identified the TSC2 tumor suppressor as a GAP (GTPase activating protein; off switch) for the Ras-like GTPase, Rheb, and demonstrated that Rheb activates the mTOR/ S6K pathway. This suggested that upon PTEN or TSC2 loss, Rheb will become constitutively activated. Indeed, we find Rheb-GTP levels are halved upon re-expression of PTEN in PTEN-deficient glioblastoma cells. Interestingly, Rheb is farnesylated and its biological activity is inhibited by the farnesyl transferase inhibitors (FTIs) previously designed to block Ras action. Our central hypothesis is that deregulated Rheb activity, resulting from PTEN loss, promotes abnormal cell growth that contributes to tumor progression. We further propose that this transforming activity can be attenuated by FTIs. To test this hypothesis, in Aim 1, we will demonstrate that dominant inhibitory Rheb mutants, Rheb RNAi and FTIs can inhibit S6 kinase activation and the proliferation of human glioma cells. In Aim 2, we will use xenograft and intracranial mouse tumor models to determine the ability of these approaches to inhibit tumor growth. In Aim 3, we will use our established assays to identify the guanine nucleotide exchange factor (GEF) responsible for turning Rheb on. Identification of this GEF and the pathway that regulates it will provide a better understanding of Rheb's cellular function and identify additional avenues to disrupt its activity. We will also determine if the Rheb-related GTPase, Rheb2, is similarly regulated by TSC2 and GEFs and if it functions in a similar manner to Rheb. Together these studies will provide valuable new information on the mechanisms of Rheb activation and its role in cell growth regulation/ tumorigenesis. They will address the molecular basis of non-Ras action of FTIs and demonstrate the value of targeting Rheb in cancer therapy.

描述（由申请人提供）：PTEN肿瘤抑制因子的缺失通常与脑肿瘤的恶性进展相关。 这种脂质磷酸酶在调节PI 3 K/Akt信号传导中发挥关键作用，PI 3 K/Akt信号传导通过TSC 2激活mTOR/S6 K途径。 我们最近确定了TSC 2肿瘤抑制因子作为Ras样GTdR，Rheb的GAP（GTdR激活蛋白;关闭开关），并证明Rheb激活mTOR/S6 K通路。 这表明，在PTEN或TSC 2丢失时，Rheb将变得组成性激活。 事实上，我们发现在PTEN缺陷的胶质母细胞瘤细胞中重新表达PTEN后，Rheb-GTP水平减半。 有趣的是，Rheb是法尼基化的，其生物活性被先前设计用于阻断Ras作用的法尼基转移酶抑制剂（FTIs）抑制。 我们的中心假设是，由于PTEN丢失导致的Rheb活性失调，促进了异常细胞生长，从而导致肿瘤进展。 我们进一步提出，这种转化活性可以减弱FTIs。 为了验证这一假设，在目的1中，我们将证明显性抑制性Rheb突变体、Rheb RNAi和FTIs可以抑制S6激酶活化和人胶质瘤细胞的增殖。 在目标2中，我们将使用异种移植物和颅内小鼠肿瘤模型来确定这些方法抑制肿瘤生长的能力。 在目标3中，我们将使用我们建立的检测方法来鉴定负责开启Rheb的鸟嘌呤核苷酸交换因子（GEF）。鉴定该GEF及其调节途径将更好地了解Rheb的细胞功能，并确定破坏其活性的其他途径。 我们还将确定Rheb相关的GTdR，Rheb 2，是否类似地受到TSC 2和GEF的调节，以及它是否以类似于Rheb的方式发挥作用。 这些研究将为Rheb激活机制及其在细胞生长调节/肿瘤发生中的作用提供有价值的新信息。 他们将解决FTIs的非Ras作用的分子基础，并证明靶向Rheb在癌症治疗中的价值。