Dys-regulation of the MnSOD-Ac-ROS-HIF2a axis promotes IR / Cisplatin resistance phenotype

MnSOD-Ac-ROS-HIF2a 轴的失调促进 IR/顺铂耐药表型

基本信息

批准号：
9262705
负责人：
David Gius
金额：
$ 39.65万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262705
关键词：
Acetylation Address Affect Agar Allografting Applications Grants Biochemistry Cell physiology Cells Cellular biology Chemical Exposure Cisplatin Complex Cytotoxic Chemotherapy Data Deacetylation Drug Metabolic Detoxication Enzymes Equilibrium Event Exhibits Genetic Genomic Instability Growth In Vitro Ionizing radiation Laboratories Lead Link Lysine Malignant Neoplasms Metabolic Metabolic stress Methods Mitochondria Modeling Modification Molecular Biology Mus Oncogenic Oncoproteins Oxidative Stress Pathway interactions Peroxidases Phenotype Physiological Post-Translational Protein Processing Process Protein Acetylation Proteins Radiation exposure Radioresistance Reactive Oxygen Species Research Proposals Resistance Role SOD2 gene Series Signal Transduction Site Superoxides Techniques Therapeutic Tumor Suppressor Proteins Tumor stage Validation Xenograft Model Xenograft procedure base chemotherapeutic agent density in vivo innovation knock-down mimetics mitochondrial metabolism mouse model mutant neoplastic cell novel therapeutic intervention overexpression permissiveness prevent radioresistant targeted treatment tissue/cell culture tumor tumor initiation tumorigenesis

项目摘要

Summary - Metabolic stress, a hallmark of cancer, is an early event in tumorigenesis that accumulates in the cell from endogenous processes, exogenous conditions, and/or agents that induce oxidative stress. Additionally, the aberrant accumulation of reactive oxygen species (ROS), as well as altered mitochondrial metabolism (i.e., oxidative or metabolic stress), are early events in the process of cellular reprogramming that under specific conditions leads to tumor cell resistance. It has become increasingly clear that lysine acetylation (i.e., mitochondrial Acetylome) is the primary post-translational modification employed by the mitochondrial to sense changes in ROS and/or metabolic conditions and initial adaptive or reparative signaling processes, including metabolic reprogramming to maintain homeostatic poise. While a link between the dysregulation of the mitochondrial Acetylome, ROS detoxification (i.e., metabolic stress), and metabolic reprogramming leading to tumor cell resistance has long been suggested, rigorous mechanistic data to supporting this intriguing idea has been limited. In this grant application it is proposed that the acetylation status of manganese superoxide dismutase (MnSOD), a critical mitochondrial enzyme, directs detoxification activity as well as connects metabolic stress and mitochondrial reparative pathways that maintain metabolic fidelity. In this regard, it is proposed that MnSOD exhibits a dichotomous function, based on the acetylation status of K68, where the homotetrameric form acts as a protective detoxification enzyme against aberrant ROS levels. In contrast, K68 acetylation inhibits the homotetrameric complex and MnSOD subsequently forms a monomeric protein form that is proposed to function as an oncoprotein. Thus, it is proposed that the dysregulation MnSOD axis, due to acetylation, alters MnSOD function which subsequently reprograms mitochondria resulting in a tumor cell anti-cancer resistance therapy phenotype. In addition, targeted the acetylation status or restoring the MnSOD functions will be used to generate and validation of new therapeutic strategies to sensitize tumor cells to cytotoxic therapies

摘要 - 代谢压力是癌症的标志，是肿瘤发生的早期事件从内源过程，外源性条件和/或或/或或/或药物中积聚在细胞中诱导氧化应激。此外，活性氧（ROS）的异常积累，以及改变的线粒体代谢（即氧化或代谢应激），也是早期事件细胞重编程的过程在特定条件下导致肿瘤细胞耐药性。越来越清楚的是，赖氨酸乙酰化（即线粒体乙酰基团）是线粒体采用的主要翻译后修饰，以感知ROS的变化和/或代谢条件以及初始自适应或修复信号传导过程，包括代谢重编程以保持体内平衡。而失调之间的联系线粒体乙酰基团，ROS排毒（即代谢应激）和代谢长期以来，重新编程导致肿瘤细胞耐药性，严格的机理支持这个有趣想法的数据受到限制。在此赠款申请中，建议锰超氧化物歧化酶（MNSOD）的乙酰化状态，一种关键的线粒体酶，指导排毒活性，并连接代谢应力和线粒体维持代谢保真度的修复途径。在这方面，有人提出MNSOD 基于K68的乙酰化状态，表现出二分函数形式充当了针对异常ROS水平的保护性解毒酶。相比之下，K68 乙酰化抑制同型复合物，MNSOD随后形成单体蛋白质形式被提议充当癌蛋白。因此，有人提出失调MNSOD轴，由于乙酰化，改变了MNSOD函数，随后，该功能随后重编程线粒体导致肿瘤细胞抗癌疗法表型。在此外，针对乙酰化状态或还原MNSOD功能将用于生成并验证新的治疗策略，以使肿瘤细胞对细胞毒性疗法敏感