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Targeting the Novel PI5P4K Pathway to Induce Glioblastoma Senescence

靶向新的 PI5P4K 途径诱导胶质母细胞瘤衰老

基本信息

批准号：
8935962
负责人：
Atsuo Sasaki
金额：
$ 32.98万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8935962
关键词：
Affinity Animals Binding Biochemical Biological Cell Aging Cell Culture Techniques Cell Line Cell Proliferation Cells Chemicals Detection Disease Ectopic Expression Enzymes Family GTP Binding Glioblastoma Goals Growth Guanine Nucleotides Guanosine Triphosphate Human In Vitro Kinetics Laboratories Lead Malignant - descriptor Mediating Metabolism Modality Modeling Molecular Monitor Mus Neuroglia Outcome Pathway interactions Patients Phenotype Phosphatidylinositols Phosphotransferases Physiological Play Primary Brain Neoplasms Property Protein Isoforms Resistance Roentgen Rays Role Signal Transduction Specificity Specimen System Testing Therapeutic Tumor Suppressor Proteins X-Ray Crystallography Xenograft Model cell growth cell growth regulation clinically relevant high throughput screening implantation improved in vitro activity in vivo inhibitor/antagonist innovation inorganic phosphate novel novel strategies novel therapeutics phosphatidylinositol 5-phosphate prevent public health relevance senescence small hairpin RNA small molecule tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Cellular senescence is a tumor suppressor mechanism. However glioblastoma multiforme (GBM), the most malignant primary brain tumor with a median survival of about one year, is highly resistant to senescence. There is a critical need for new therapeutic modalities and agents that sensitize GBM to senescence to improve patient outcome. A family of PI5P4K phosphorylates phosphatidylinositol 5-phosphate (PI5P) and converts it to phosphatidylinositol 4,5-phosphate (PI[4,5]P2) to regulate phosphoinositide signaling. In the preliminary studies, my laboratory found that PI5P4K�inds directly to guanine nucleotides. Our X-ray structural analyses show that PI5P4K�tilizes GTP as the preferred phospho-donor, as opposed to ATP. Kinetic analyses also predict that physiological GTP levels control the PI5P4K�ctivity. Importantly, we have found that cellular GTP levels play critical rol in suppressing GBM senescence and that PI5P4K�nockdown triggers senescence of GBM cells. We have identified a small chemical compound that inhibits PI5P4K activity in vitro and in vivo. The treatment of the PI5P4K chemical inhibitor induces senescence of GBM cells. These results indicate that inhibitors of PI5P4K�ould be useful in preventing or treating GBM. The goal of this proposal is to determine the significance of a novel type of GTP-dependent kinase, PI5P4K�in regulating GBM senescence, and to determine whether inhibition of PI5P4K�ould induce GBM senescence and reduce its tumorigenic activity in vitro and in vivo. To test the hypothesis, we will determine the role of PI5P4K�n GBM cell growth by shRNA-mediated PI5P4K�nockdown and pharmacological inhibition using in vitro cell culture and a clinically relevant orthotopic implantation model of glioblastoma (Aim 1). We will use biochemical and biological analyses to determine the mechanism of GTP detection by PI5P4K�Aim 2). We will determine how PI5P4K�egulates senescence by characterizing PI5P4K�ownstream effectors (Aim 3). Collectively, these studies will lead to reveal the novel mechanism and opportunity for inducing senescence and growth arrest of glioblastoma cells by targeting PI5P4K�

描述（由申请人提供）：细胞衰老是一种肿瘤抑制机制。然而，多形性胶质母细胞瘤（GBM）是最恶性的原发性脑肿瘤，中位生存期约为一年，对衰老具有高度抗性。迫切需要使GBM对衰老敏感以改善患者结果的新治疗方式和药剂。PI 5 P4 K家族使磷脂酰肌醇5-磷酸（PI 5 P）磷酸化并将其转化为磷脂酰肌醇4，5-磷酸（PI[4，5]P2）以调节磷酸肌醇信号传导。在初步研究中，我实验室发现PI 5 P4 K直接与鸟嘌呤核苷酸有关。我们的X射线结构分析表明，PI 5 P4 K利用GTP作为首选的磷酸供体，而不是ATP。动力学分析还预测，生理GTP水平控制PI 5 P4 K活性。重要的是，我们发现细胞GTP水平在抑制GBM衰老中起关键作用，PI 5 P4 K敲低触发GBM细胞衰老。我们已经确定了一种小的化合物，抑制PI 5 P4 K活性在体外和体内。PI 5 P4 K化学抑制剂的处理诱导GBM细胞的衰老。这些结果表明，PI 5 P4 K β抑制剂可用于预防或治疗GBM。本研究的目的是确定一种新型的GTP依赖性激酶PI 5 P4 K β在调节GBM衰老中的意义，并确定抑制PI 5 P4 K β是否会诱导GBM衰老并降低其体外和体内致瘤活性。为了验证这一假设，我们将使用体外细胞培养和临床相关的胶质母细胞瘤原位植入模型（Aim 1），通过shRNA介导的PI 5 P4 K敲低和药理学抑制来确定PI 5 P4 K在GBM细胞生长中的作用。我们将使用生物化学和生物学分析来确定通过PI 5 P4 K-Aim 2）检测GTP的机制。我们将通过表征PI 5 P4 K的下游效应子来确定PI 5 P4 K是如何调节衰老的（目的3）。总之，这些研究将揭示通过靶向PI 5 P4 K诱导胶质母细胞瘤细胞衰老和生长停滞的新机制和机会。