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