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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-代谢应激是癌症的标志，是肿瘤发生的早期事件，从内源性过程、外源性条件和/或诱导氧化应激。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），是早期事件，在特定条件下导致肿瘤细胞抗性的细胞重编程过程。越来越清楚的是赖氨酸乙酰化（即，线粒体乙酰基组）是线粒体用于感知ROS变化的初级翻译后修饰和/或代谢状况和初始适应性或修复性信号传导过程，包括代谢重编程以维持体内平衡。虽然调节失调与线粒体乙酰组，ROS解毒（即，代谢应激）和代谢导致肿瘤细胞抗性的重编程长期以来一直被认为是严格的机制，支持这一有趣想法的数据有限。在这份补助金申请中，建议线粒体关键酶锰超氧化物歧化酶（MnSOD）乙酰化状态酶，指导解毒活动，以及连接代谢应激和线粒体维持代谢保真度的修复途径。在这方面，建议MnSOD 基于K68的乙酰化状态，显示二分功能，其中同源四聚体形式作为保护性解毒酶对抗异常的ROS水平。相比之下，K68 乙酰化抑制同源四聚体复合物和MnSOD随后形成单体一种被认为起癌蛋白作用的蛋白质形式。因此，建议由于乙酰化，MnSOD轴的失调改变了MnSOD的功能，重编程线粒体，导致肿瘤细胞抗癌抗性治疗表型。在此外，针对乙酰化状态或恢复MnSOD功能将用于产生和验证使肿瘤细胞对细胞毒性疗法敏感的新治疗策略