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肿瘤抑制剂的丧失经常与脑肿瘤的恶性进展有关。 该脂质磷酸酶在调节PI3K/AKT信号中起关键作用，该信号通过TSC2激活MTOR/S6K途径。 我们最近将TSC2肿瘤抑制剂确定为RAS样GTPase Rheb的间隙（GTPase激活蛋白； OFF开关），并证明RHEB激活MTOR/ S6K途径。 这表明在PTEN或TSC2损失后，Rheb将被组成式激活。 实际上，我们发现在PTEN缺乏胶质母细胞瘤细胞中PTEN重新表达PTEN时，RHEB-GTP水平减半。 有趣的是，Rheb是Farnesylation的，其生物学活性受到先前旨在阻止RAS作用的Farnesyl转移酶抑制剂（FTI）抑制。 我们的中心假设是，由PTEN丧失导致的放松调节的RHEB活性促进了异常的细胞生长，从而有助于肿瘤进展。 我们进一步建议，FTI可以减弱这种转化活动。 为了检验这一假设，在AIM 1中，我们将证明主要的抑制性RHEB突变体，Rheb RNAi和FTI可以抑制S6激酶激活和人神经胶质瘤细胞的增殖。 在AIM 2中，我们将使用异种移植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AIM 3中，我们将使用我们既定的测定法确定负责打开Rheb的鸟嘌呤核苷酸交换因子（GEF）。 识别该GEF和调节的途径将更好地了解Rheb的细胞功能，并确定其他途径破坏其活性。 我们还将确定与RHEB相关的GTPase Rheb2是否受TSC2和GEFS类似的调节，以及它是否以与Rheb相似的方式起作用。 这些研究将共同​​提供有关RHEB激活机制及其在细胞生长调节/肿瘤发生中的作用的宝贵新信息。 他们将解决FTI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。