Regulation of Tumorigenesis and therapeutic resistance by Nrf2 in lung cancer

描述（由申请人提供）：肺癌是世界范围内最常见的癌症相关死亡原因，非小细胞肺癌（NSCLC）细胞的内在治疗耐药性仍然是提高癌症治疗有效性的主要挑战。核因子红细胞-2相关因子-2 （Nrf2）是一种氧化还原敏感转录因子，调节亲电/外源解毒酶和药物外排蛋白的表达，并在正常细胞中对氧化应激和凋亡具有细胞保护作用。kelch样ech相关蛋白（Keap1）通过靶向Nrf2蛋白酶体降解来负性调节Nrf2活性。我们最近报道了Keap1双等位基因失活导致NSCLC中Nrf2功能的组成性激活。初步研究表明，Nrf2在肺癌细胞中的组成性激活增加了中枢代谢途径的活性，促进了体内肿瘤的生长，并有助于化疗耐药。因此，我们假设由于Keap1活性的丧失而导致的Nrf2功能的获得促进了肿瘤的发生，并赋予了治疗抗性，野生型Keap1通过抑制Nrf2的活性而发挥肿瘤抑制作用。特异性目的1：验证Nrf2功能的增强促进肺肿瘤发生的假设（在致癌信号存在的情况下）。特异性目的2：验证在高Nrf2水平的NSCLC细胞中恢复野生型Keap1功能会减弱Nrf2活性并抑制肿瘤生长的假设。特异性目的3：验证Nrf2在肺癌细胞中功能的获得，通过戊糖磷酸途径和促进肿瘤生长所必需的三羧酸循环增加葡萄糖通量的假设。特异性目的：验证Nrf2功能增强阻断NSCLC细胞中依赖于Nrf2的磷酸途径酶（葡萄糖-6磷酸脱氢酶和转酮醇酶）活性抑制肿瘤生长和减轻化疗耐药的假设。这些目标将有助于通过新的途径了解肺肿瘤发生的调控，并制定针对该途径的策略来规避治疗耐药性。

DESCRIPTION (provided by applicant): Lung cancer is the most common cause of cancer-related death worldwide and intrinsic therapeutic resistance of non small cell lung cancer (NSCLC) cells remains a major challenge in improving the effectiveness of cancer therapy. Nuclear factor erythroid-2 related factor-2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile/ xenobiotic detoxification enzymes and drug efflux proteins and confers cytoprotection against oxidative stress and apoptosis in normal cells. Kelch-like ECH-associated protein (Keap1) negatively regulates Nrf2 activity by targeting it for proteasomal degradation. We recently reported that biallelic inactivation of Keap1 results in constitutive activation of Nrf2 function in NSCLC. Preliminary studies indicate that constitutive activation of Nrf2 in lung cancer cells increases activity of central metabolic pathways, promotes in vivo tumor growth and contributes to chemoresistance. Thus, we hypothesize that the gain of Nrf2 function resulting from the loss of Keap1 activity promotes tumorigenesis and confers therapeutic resistance and wild type Keap1 functions as a tumor suppressor by inhibiting the activity of Nrf2. Specific Aim 1: To test the hypothesis that the gain of Nrf2 function promotes lung tumorigenesis (in the presence of an oncogenic signal). Specific Aim 2: To test the hypothesis that restoring wild type Keap1 function in NSCLC cells with high Nrf2 levels attenuates Nrf2 activity and suppresses tumor growth. Specific Aim 3: To test the hypothesis that the gain of Nrf2 function in lung cancer cells increases glucose flux through pentose phosphate pathway and Tricarboxylic acid cycle essential for promoting tumor growth. Specific Aim: To test the hypothesis that blocking the activity of Nrf2-dependent phosphate pathway enzymes (Glucose-6 phosphate dehydrogenase and Transketolase) in NSCLC cells with gain of Nrf2 function inhibits tumor growth and attenuates chemoresistance. These aims will help in understanding the regulation of lung tumorigenesis by a novel pathway and develop a strategy for targeting this pathway to circumvent therapeutic resistance. PUBLIC HEALTH RELEVANCE: The studies proposed in this project have potential for developing new means to inhibit tumor progression and chemoresistance. Successful completion of this project will develop a new therapeutic strategy for lung cancer treatment.