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

• 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
• 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

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-代谢应激是癌症的一个标志，是肿瘤发生的早期事件， 通过内源性过程、外源性条件和/或以下因素在细胞中积累 诱导氧化应激。此外，活性氧物种(ROS)的异常积累， 以及线粒体代谢改变(即氧化或代谢应激)，都是 在特定条件下导致肿瘤细胞耐药的细胞重编程过程。 越来越清楚的是，赖氨酸乙酰化(即线粒体乙酰化)是 线粒体用来感知ROS变化的初级翻译后修饰 和/或代谢条件和初始适应或修复信号过程，包括 新陈代谢重新编程以维持体内平衡平衡。而监管失调之间的联系 线粒体乙酰组、ROS解毒(即代谢应激)和代谢 长期以来，重新编程导致肿瘤细胞耐药一直被认为是严格的机制 支持这一耐人寻味的想法的数据有限。在这项赠款申请中，建议 线粒体关键酶--锰超氧化物歧化酶的乙酰化状态 酶，指导解毒活性，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，建议将MnSOD 基于K68的乙酰化状态，显示出二分功能，其中同源四聚体 Form作为一种保护性解毒酶来对抗异常的ROS水平。相比之下，K68 乙酰化抑制同源四聚体复合体，而MnSOD随后形成单体 被认为具有癌蛋白功能的蛋白质形式。因此，建议将 由于乙酰化引起的MnSOD轴调节失调，改变了MnSOD的功能，从而 线粒体重新编程，形成肿瘤细胞抗癌耐药治疗表型。在……里面 此外，针对乙酰化状态或恢复MnSOD功能将用于生成 以及验证使肿瘤细胞对细胞毒治疗敏感的新治疗策略