INVESTIGATING NAPDH OXIDASES AND REDOX SIGNALING IN LUNG CANCER TUMORIGENICITY

项目摘要 肺癌导致的癌症相关死亡人数是美国最多的。非小细胞肺 癌症(NSCLC)患者肿瘤过度表达NADPH氧化酶，产生细胞内过氧化氢 (H_2O_2)，在肺癌的发生发展中起重要作用。到目前为止，我们的初步结果表明 NOX活性在NCSLC转化、逃逸失巢、磷酸化等过程中起重要作用 几种新的胞内蛋白中半胱氨酸的信号传递和氧化还原调节。这样做的根本目的是 建议研究肺癌生物学中NOX依赖的氧化还原信号的分子细节。目标1 该提案将表征NOX亚型在肺癌患者肺肿瘤中过度表达的功能作用。 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依赖的激酶活性来确定活性。目标3将定量绘制氮氧化物的半胱氨酸靶标- NSCLC中产生的过氧化氢对NOX的抑制。研究NOX酶和氧化还原信号在细胞周期中的作用 肺癌将揭示调控癌细胞生长、转化和转移的正交控制机制 逃避阿尼基斯。RAS突变、NOX过度表达和ROS增加之间有很强的联系 制作。因此，研究非小细胞肺癌中的氧化还原信号可能会发现新的调节因子和治疗方法。 肺癌的干预目标，特别是没有明确治疗选择的RAS驱动的肿瘤。

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.