INVESTIGATING NAPDH OXIDASES AND REDOX SIGNALING IN LUNG CANCER TUMORIGENICITY

研究肺癌致瘤性中的 NAPDH 氧化酶和氧化还原信号传导

• 批准号: 9175407
• 负责人: Jason M. Held
• 金额: $ 34.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175407
• 关键词: Affect; Anoikis; Behavior; Cancer Biology; Cancer Cell Growth; Cancer Patient; Cancer cell line; Cell Line; Cessation of life; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Cysteine; DNA; DNA Sequence Alteration; Data Set; Disease; Enzymes; Epidermal Growth Factor Receptor; Epithelial; Family; Family member; Genes; Genomics; Goals; Growth; Hydrogen Peroxide; Intervention; KRAS2 gene; Label; Length; Light; Link; Location; Lung; Lung Neoplasms; MAP Kinase Gene; MAPK8 gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mesenchymal; Molecular; Mutagenesis; Mutation; NADPH Oxidase; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenic; Organelles; Oxidases; Oxidation-Reduction; Patients; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Production; Protein Isoforms; Proteins; Reactive Oxygen Species; Regulation; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Site; Source; Sulfenic Acids; Testing; The Cancer Genome Atlas; Therapeutic; Transformed Cell Line; Tumor Biology; Tumorigenicity; United States; Xenograft procedure; base; cancer cell; cancer therapy; in vivo; inhibitor/antagonist; interest; knock-down; mutant; mutational status; novel; overexpression; oxidation; protein expression; resistance mechanism; second messenger; sensor; therapeutic target; tumor; tumorigenesis

Project Summary Lung cancer results in the largest number of cancer-related deaths in the United States. Non-small cell lung cancer (NSCLC) patient tumors overexpress NADPH oxidases that produce intracellular hydrogen peroxide (H2O2) and play an important role in lung cancer tumorigenicity. To date, our preliminary results demonstrate that NOX activity is functionally important for NCSLC transformation, escape from anoikis, phosphorylation signaling, and redox regulation of cysteines in several novel intracellular proteins. The fundamental goal of this proposal is to study the molecular details of NOX-dependent redox signaling in lung cancer biology. Aim 1 of the proposal will characterize the functional role of NOX isoforms overexpressed in lung patient tumors in lung cancer tumorigenicity. Aim 2 will examine the regulatory crosstalk between phosphorylation signaling and NOX activity by profiling NOX-dependent kinase activity. Aim 3 will quantitatively map the cysteine targets of NOX- derived H2O2 in NSCLC upon NOX inhibition. Investigating the role of NOX enzymes and redox signaling in lung cancer will shed light on orthogonal control mechanisms regulating cancer cell growth, transformation and evasion of anoikis. There is a strong link between RAS mutations, overexpression of NOX and increased ROS production. Therefore, investigating redox signaling in NSCLC may identify new regulators and therapeutic targets for intervention in lung cancer, especially RAS-driven tumors with no clear therapeutic option.

项目摘要 在美国，肺癌导致癌症相关的死亡人数最多。非小细胞肺 癌症（NSCLC）患者肿瘤过表达的NADPH氧化酶，产生细胞内氢过氧化 （H2O2）并在肺癌肿瘤性中起重要作用。迄今为止，我们的初步结果证明了 NOX活性在功能上对于NCSLC转化，逃避ANOIKI，磷酸化很重要 信号传导和几种新型细胞内蛋白质中半胱氨酸的氧化还原调节。这个基本目标 建议是研究肺癌生物学中NOX依赖性氧化还原信号传导的分子细节。目标1 该提案将表征NOX同工型在肺中肺部患者肿瘤中过表达的功能作用 癌症肿瘤性。 AIM 2将检查磷酸化信号和NOX之间的调节串扰 通过分析NOX依赖性激酶活性的活性。 AIM 3将定量绘制NOX-的半胱氨酸靶标 NOx抑制后NSCLC中衍生的H2O2。研究NOX酶和氧化还原信号在中的作用 肺癌将阐明调节癌细胞生长，转化和的正交控制机制 逃避Anoikis。 RAS突变，NOX的过表达和ROS增加之间存在很强的联系 生产。因此，研究NSCLC中的氧化还原信号传导可能会识别新调节剂和治疗剂 干预肺癌的靶标，尤其是RAS驱动的肿瘤，没有明确的治疗选择。