P53-dependent GSTP1 Gene Regulation and Glioma Drug Resistance

P53 依赖性 GSTP1 基因调控和神经胶质瘤耐药性

基本信息

批准号：
8657883
负责人：
FRANCIS ALI-OSMAN
金额：
$ 30.65万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657883
关键词：
Antineoplastic Agents Apoptotic Automobile Driving Binding Biology Cell Line Cell Survival Cell physiology Cells Cellular Stress Chemotherapy-Oncologic Procedure Clinical Research Complex Conflict (Psychology)DNA Data Down-Regulation Drug resistance Exons GSTP1 gene Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genome Genomics Glioblastoma Glioma Glutathione S-Transferase Growth Heterogeneity Human In Vitro Indium Light MDM2 gene Malignant Neoplasms Mediating Metabolic Metabolism Mitogen-Activated Protein Kinases Modeling Mutate Mutation Outcome Pathway interactions Patients Phase Phenotype Protein p53 Proteins Regulation Research Resistance Role Signal Transduction Signaling Protein Specimen Staging TP53 gene Testing Transactivation Transcript Transcriptional Activation Transcriptional Regulation Treatment Efficacy Treatment Failure Treatment outcome Xenograft procedure activating transcription factor base cancer therapy chemotherapeutic agent chemotherapy design drug metabolism gain of function improved in vivo inhibitor/antagonist insight mutant neoplastic cell novel novel strategies novel therapeutics preclinical evaluation preclinical study public health relevance research clinical testing response treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Glioblastomas (GBMs) are among the deadliest and least responsive of human tumors to therapy. The mechanisms driving GBM drug resistance are, however, still not well understood, thus making it difficult to design more effective strategies and/or to develop novel therapeutics to overcome this resistance. Glutathione S-transferase P1, GSTP1, a multifunctional protein involved in phase II metabolism and in the regulation of cell signaling is frequently highly expressed in GBM and a large number of preclinical and clinical studies have shown it to be a major determinant of tumor drug resistance, treatment failure and poor patient survival. p53 encodes a transcription factor activated by a variety of cellular stresses, including, those inflicted by anti-cancer agents. Once activated, p53 acts in a complex cellular network triggering a cascade of downstream pathways to protect genomic integrity of the cell. Mutations in the p53 gene, both inactivating and gain-of-function, are among the most common genetic defects in human cancer, including, GBM. Consequently, p53 mutational status has been intensively investigated, both preclinically and in clinical studies, for its role in tumor response to therapy. These studies, however, have yielded mixed results, with some showing a strong correlation between the presence of p53 mutations and drug resistance while others have shown that wild-type p53, rather than the mutated form, is associated with drug resistance. This apparent conflicting role of p53 in tumor drug resistance reflects the complexity of the p53 network, the functional heterogeneity of p53 mutations and the fact that the full spectrum of downstream p53 targets has not been fully characterized. Recently, we made the provocative finding that the human GSTP1 gene contains a functional canonical p53 binding motif and is transcriptionally activated by p53 in tumor cells. The crosstalk between p53 and GSTP1 could thus be a major component of the cellular function of these two genes and their encoded proteins, particularly, in the protection of the cellular genome against genotoxic compounds, many of which are GSTP1 substrates. A better understanding and characterization of the p53-GSTP1 interaction will provide important insights into the biology of the resistance phenotype and a basis for developing novel strategies to improve the outcome of chemotherapy. The findings might also shed light on the underlying basis of the apparent conflicting relationship between p53 status and outcome of cancer chemotherapy and the increasing recognition of a critical role for p53 in cellular metabolism. The hypothesis to be tested is that transcriptional activation of the GSTP1 gene by wild-type 53 and gain-of-function p53 mutants will increase GSTP1 gene expression, resulting in enhanced GSTP1-mediated drug metabolism and downstream inhibition of MAP kinase signaling leading to more aggressive growth and a drug resistant phenotype in glioblastomas. The Specific Aims to test this novel hypothesis of tumor drug resistance are: Aim 1. Determine the relationship between p53 gene status and transcriptional activity of the GSTP1 gene in GBM; Aim 2. Investigate the functional and mechanistic basis for the p53-dependent transcriptional regulation of the GSTP1 gene in GBM cells and Aim 3. Investigate the impact of the p53-GSTP1 crosstalk on drug resistance in GBM and examine whether this can be targeted to improve therapeutic efficacy in glioblastoma.

描述（由申请人提供）：胶质母细胞瘤（GBM）是最致命且对治疗反应最差的人类肿瘤之一。然而，驱动 GBM 耐药性的机制仍不清楚，因此很难设计更有效的策略和/或开发新的疗法来克服这种耐药性。谷胱甘肽S-转移酶P1、GSTP1是一种参与II期代谢和细胞信号传导调节的多功能蛋白，在GBM中频繁高表达，大量临床前和临床研究表明它是肿瘤耐药的主要决定因素、治疗失败和患者生存率低。 p53 编码一种由多种细胞应激激活的转录因子，包括抗癌药物造成的应激。一旦激活，p53 就会在复杂的细胞网络中发挥作用，触发一系列下游途径，以保护细胞基因组的完整性。 p53 基因突变（包括失活突变和功能获得突变）是人类癌症（包括 GBM）中最常见的遗传缺陷之一。因此，p53 突变状态在临床前和临床研究中都得到了深入研究，以了解其在肿瘤治疗反应中的作用。然而，这些研究得出的结果好坏参半，其中一些研究显示p53突变的存在与耐药性之间存在很强的相关性，而另一些研究则表明野生型p53而不是突变形式与耐药性相关。 p53 在肿瘤耐药性中这种明显的矛盾作用反映了 p53 网络的复杂性、p53 突变的功能异质性以及下游 p53 靶标的全谱尚未完全表征的事实。最近，我们做出了一个令人兴奋的发现，即人类 GSTP1 基因包含一个功能性规范 p53 结合基序，并且在肿瘤细胞中被 p53 转录激活。因此，p53 和 GSTP1 之间的串扰可能是这两个基因及其编码蛋白的细胞功能的主要组成部分，特别是在保护细胞基因组免受基因毒性化合物（其中许多是 GSTP1 底物）的影响中。更好地理解和表征 p53-GSTP1 相互作用将为了解耐药表型的生物学提供重要见解，并为开发改善化疗效果的新策略奠定基础。这些发现还可能揭示 p53 状态与癌症化疗结果之间明显矛盾关系的根本基础，以及人们日益认识到 p53 在细胞代谢中的关键作用。要测试的假设是野生型 53 和功能获得性 p53 突变体对 GSTP1 基因的转录激活将增加 GSTP1 基因表达，从而增强 GSTP1 介导的药物代谢和下游 MAP 激酶信号传导抑制，从而导致更多胶质母细胞瘤的侵袭性生长和耐药表型。检验这一新的肿瘤耐药假说的具体目的是：目的 1. 确定 GBM 中 p53 基因状态与 GSTP1 基因转录活性之间的关系；目标 2. 研究 GBM 细胞中 GSTP1 基因的 p53 依赖性转录调控的功能和机制基础；目标 3. 研究 p53-GSTP1 串扰对 GBM 耐药性的影响，并检查是否可以有针对性地改善这种影响胶质母细胞瘤的治疗效果。