Regulation of Tumorigenesis and therapeutic resistance by Nrf2 in lung cancer

描述(申请人提供)：肺癌是全球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。核因子红细胞相关因子-2(Nrf2)是一种氧化还原敏感的转录因子，在正常细胞中调节亲电/异物解毒酶和药物外排蛋白的表达，对氧化应激和细胞凋亡具有保护作用。Kelch样ECH相关蛋白(Keap1)通过靶向蛋白酶体降解来负向调节Nrf2的活性。我们最近报道，在非小细胞肺癌中，Keap1的双等位基因失活导致Nrf2功能的结构性激活。初步研究表明，肺癌细胞中Nrf2的结构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，并促进了化疗耐药。因此，我们假设，由于Keap1活性的丧失而导致的Nrf2功能的增强促进了肿瘤的发生，并赋予了治疗耐药性，而野生型Keap1通过抑制Nrf2的活性而发挥肿瘤抑制作用。具体目标1：检验Nrf2功能的获得促进肺肿瘤发生的假设(在存在致癌信号的情况下)。特定目的2：验证在高Nrf2水平的NSCLC细胞中恢复野生型Keap1功能可减弱Nrf2活性并抑制肿瘤生长的假说。具体目的3：验证肺癌细胞中Nrf2功能增强通过磷酸戊糖途径和三羧酸循环增加葡萄糖通量的假说，这是促进肿瘤生长所必需的。目的：验证阻断非小细胞肺癌细胞中依赖于Nrf2的磷酸途径酶(葡萄糖-6磷酸脱氢酶和转酮醇酶)的活性同时获得Nrf2功能可抑制肿瘤生长和减轻化疗耐药的假说。这些目的将有助于理解一种新的途径对肺肿瘤发生的调控，并开发一种针对这一途径的策略，以规避治疗耐药。

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.