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

• 批准号: 8245147
• 负责人: FRANCIS ALI-OSMAN
• 金额: $ 31.6万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/8245147
• 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

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. PUBLIC HEALTH RELEVANCE: GBMs are characterized by a high rate of p53 mutations and high GSTP1 expression, both of which impact on treatment outcome. The results of this research will provide a basis for novel GBM treatment strategies. This is significant and timely, given the current lack of effective GBM therapies and that both p53 and GSTP1 inhibitors are being actively being developed and are in various stages of preclinical and clinical evaluation.

描述(由申请人提供)：胶质母细胞瘤(GBM)是人类肿瘤中对治疗最致命和最不敏感的肿瘤之一。然而，导致GBM耐药的机制仍不清楚，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。谷胱甘肽S转移酶P1是一种多功能蛋白，参与II期代谢和细胞信号调节，在基底膜中经常高表达，大量临床前和临床研究表明，它是肿瘤耐药、治疗失败和患者生存不良的主要决定因素。P53编码一种转录因子，由各种细胞应激激活，包括抗癌剂造成的应激。一旦被激活，p53就会在一个复杂的细胞网络中发挥作用，触发一系列下游通路，以保护细胞的基因组完整性。P53基因的突变，包括失活和功能获得，是人类癌症中最常见的遗传缺陷之一，包括GBM。因此，P53突变状态在肿瘤治疗反应中的作用，在临床前和临床研究中都得到了广泛的研究。然而，这些研究产生了好坏参半的结果，一些研究表明p53突变的存在与耐药性之间存在强烈的相关性，而另一些研究则表明野生型p53与耐药性有关，而不是突变形式。P53在肿瘤耐药中的这种明显的相互冲突的作用反映了P53网络的复杂性，P53突变的功能异质性，以及P53下游靶点的全谱尚未被完全表征的事实。最近，我们发现人类GSTP1基因含有一个功能性的P53结合基序，并被肿瘤细胞中的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细胞功能的主要组成部分，特别是在保护细胞基因组免受遗传毒性化合物的影响方面，其中许多是GSTP1底物。更好地了解和表征P53-GSTP1的相互作用将为了解耐药表型的生物学特性提供重要的见解，并为开发新的策略来改善化疗结果奠定基础。这些发现也可能揭示P53状态和癌症化疗结果之间明显冲突关系的潜在基础，以及人们对P53在细胞代谢中关键作用的日益认识。需要检验的假设是，野生型53和功能获得型突变体对GSTP1基因的转录激活将增加GSTP1基因的表达，导致GSTP1介导的药物代谢增强和MAP激酶信号的下游抑制，从而导致胶质母细胞瘤更具侵袭性和耐药表型。目的：1.确定胶质母细胞瘤中P53基因状态与GSTP1基因转录活性之间的关系；2.研究P53依赖的GSTP1基因转录调控的功能和机制基础；3.研究P53-GSTP1串扰对胶质母细胞瘤耐药的影响，探讨其是否可以作为提高胶质母细胞瘤治疗效果的靶点。 公共卫生相关性：基底膜的特点是高P53突变率和高GSTP1表达，这两者都会影响治疗结果。本研究结果将为新的GBM治疗策略提供依据。考虑到目前缺乏有效的GBM治疗方法，以及P53和GSTP1抑制剂正在积极开发中，并处于临床前和临床评估的不同阶段，这一研究意义重大且及时。