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: 9283379
• 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/9283379
• 关键词: Affect; Anoikis; Behavior; Cancer Biology; Cancer Cell Growth; Cancer Patient; Cancer cell line; Cell Line; Cessation of life; Chemicals; Clinical; 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; Individual; 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; Oxides; 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; 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，肺癌导致的癌症相关死亡人数最多。非小细胞肺 癌症（NSCLC）患者肿瘤过表达产生细胞内过氧化氢的NADPH氧化酶 （H2O2）在肺癌的致瘤性中起重要作用。到目前为止，我们的初步结果表明， NOX活性对于NCSLC转化、逃避失巢凋亡、磷酸化具有重要功能 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。这个项目的基本目标是 该提案旨在研究肺癌生物学中NOx依赖性氧化还原信号传导的分子细节。目标1 该提案将描述在肺肿瘤患者中过表达的NOX亚型的功能作用， 癌症致瘤性。目标2将研究磷酸化信号和NOX之间的调节串扰 通过分析NOX依赖性激酶活性来测定活性。目标3将定量绘制NOx的半胱氨酸靶点， 来源于H2O2。研究NOX酶和氧化还原信号在 肺癌将阐明调节癌细胞生长、转化和 逃避失业。RAS突变、NOX过表达和ROS增加之间存在密切联系 生产因此，研究NSCLC中的氧化还原信号传导可能会发现新的调节剂和治疗剂。 肺癌的干预靶点，特别是RAS驱动的肿瘤，没有明确的治疗选择。