Regulation of Tumorigenesis and therapeutic resistance by Nrf2 in lung cancer

描述（由申请人提供）：肺癌是全球癌症相关死亡的最常见原因，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（Nrf 2）是一种氧化还原敏感性转录因子，调节亲电/异生物质解毒酶和药物外排蛋白的表达，并赋予正常细胞抗氧化应激和凋亡的细胞保护作用。Kelch样ECH相关蛋白（Keap 1）通过靶向其进行蛋白酶体降解来负调节Nrf 2活性。我们最近报道了Keap 1的双等位基因失活导致NSCLC中Nrf 2功能的组成性激活。初步研究表明，肺癌细胞中Nrf 2的组成性激活增加了中枢代谢途径的活性，促进了体内肿瘤生长并有助于化疗耐药性。因此，我们假设，由于Keap 1活性的丧失而导致的Nrf 2功能的获得促进肿瘤发生并赋予治疗抗性，并且野生型Keap 1通过抑制Nrf 2的活性而作为肿瘤抑制因子发挥功能。具体目的1：检验Nrf 2功能的获得促进肺肿瘤发生（在致癌信号存在的情况下）的假设。具体目标二：为了检验在具有高Nrf 2水平的NSCLC细胞中恢复野生型Keap 1功能减弱Nrf 2活性并抑制肿瘤生长的假设。具体目标3：为了验证肺癌细胞中Nrf 2功能的获得增加了通过磷酸戊糖途径和三羧酸循环的葡萄糖通量，这对于促进肿瘤生长至关重要的假设。具体目标：检验在NSCLC细胞中阻断Nrf 2依赖性磷酸途径酶（葡萄糖-6磷酸脱氢酶和转酮醇酶）的活性并获得Nrf 2功能可抑制肿瘤生长并减弱化疗耐药性的假设。这些目标将有助于了解一种新的途径对肺肿瘤发生的调节，并制定一种针对这一途径的策略，以规避治疗耐药性。 公共卫生相关性：该项目中提出的研究有可能开发新的方法来抑制肿瘤进展和化疗耐药性。该项目的成功完成将为肺癌治疗开发新的治疗策略。

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.