AMPK and AMPK-related kinases in lung cancer development and treatment

AMPK 和 AMPK 相关激酶在肺癌发生和治疗中的作用

• 批准号: 8984294
• 负责人: Reuben Shaw
• 金额: $ 40.26万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-16 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984294
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Affect; Animal Model; Antibodies; Antineoplastic Agents; Apoptosis; Autophagocytosis; Biguanides; Biochemical Pathway; Biological Availability; Cancer Etiology; Cancer Model; Cancer cell line; Cell Culture Techniques; Cell Death; Cell Polarity; Cellular Metabolic Process; Cessation of life; Data; Development; Diabetes Mellitus; Environment; Epidemiologic Studies; Epidemiology; Epithelial Cells; Exhibits; FRAP1 gene; Family; Family member; Genes; Genetic; Genetic Engineering; Genetically Engineered Mouse; Genotype; Glucose; Growth; Head; Homeostasis; Human; Immunocompromised Host; Individual; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolism; Metformin; Mitochondria; Modeling; Mus; Mutate; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Non-Small-Cell Lung Carcinoma; Nutrient; Oxygen; Pathway interactions; Pharmaceutical Preparations; Phenformin; Phosphorylation; Phosphotransferases; Physiological; Property; Protein Isoforms; Protein Kinase; Proteins; Research; Role; STK11 gene; Serine; Signal Pathway; Source; Stress; Subfamily lentivirinae; TP53 gene; Testing; Therapeutic; Therapeutic Effect; Threonine; Time; Tissues; Tobacco-Associated Carcinogen; Treatment Efficacy; Tumor Suppression; Tumor Suppressor Proteins; Xenograft Model; Xenograft procedure; analog; cancer cell; cancer genetics; cell growth; in vivo; inhibitor/antagonist; interest; killings; mouse model; novel therapeutics; preclinical study; preclinical trial; public health relevance; recombinase; sensor; small hairpin RNA; therapy development; tumor; tumor initiation; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): Cancer genetics has revealed that p53 and LKB1/STK11 are the most commonly mutated tumor suppressors in sporadic human non-small cell lung cancers (NSCLC), the leading source of annual cancer deaths in the U.S. LKB1/STK11 encodes a Ser/Thr protein kinase that directly phosphorylates the activation loop of the AMP-activated protein kinase (AMPK) as well as 12 poorly understood related kinases in the AMPK family. AMPK is a master regulator of cellular and organismal metabolism that acts as a sensor of cellular energy, arresting cell growth and reprogramming metabolism when ATP levels are low. Over the past 5 years, a number of labs including ours have decoded substrates of AMPK and related kinases that mediate downstream effects on growth and metabolism and may relate to the tumor suppressor activity of LKB1, including AMPK phosphorylation of core components in the mammalian target of rapamycin (mTOR) and autophagy pathways. In addition, the front-line type 2 diabetes drug metformin has been shown to regulate cell growth in an AMPK- and mTOR-dependent manner in some settings, suggesting it may serve as a potential anti-cancer agent. Despite these direct connections between AMPK and growth regulators, there is a great deal of overlap between the downstream functions and effectors of AMPK and its 12 related kinases, so it remains unclear which of these 14 kinases that LKB1 directly activates are the most critical for mediating its tumor suppressor function. Moreover, accumulating evidence suggests that in many settings the ability of AMPK to restore metabolic homeostasis under glucose or oxygen-poor conditions may promote survival of cancer cells. Thus, the role of AMPK in tumorigenesis may be very context dependent, and a different AMPK related kinase may be more important for the ability of LKB1 to suppress NSCLC. Finally, while epidemiological data and mouse xenograft and tobacco carcinogen models support a beneficial effect of metformin, this has not been examined in a genetically engineered mouse model of a human cancer in a manner that allows one to distinguish genotype-specific therapeutic effects. Moreover, metformin and its more potent analog phenformin are mitochondrial inhibitors that affect pathways outside of AMPK, and may selectively allow for the killing of LKB1-deficient tumors as is observed in cell culture models. The specific aims are to 1) define which of the 14 AMPK family kinases are essential for the ability of LKB1 to suppression tumorigenesis in a NSCLC xenograft model; 2) genetically define the role of AMPKa1 or AMPKa2 and related family kinases in a genetic engineered mouse model of NSCLC; and 3) examine the therapeutic efficacy and genotype selectivity of AMPK-activating biguanide compounds metformin and phenformin in multiple genetic engineered mouse models of NSCLC.

描述（由申请人提供）：癌症遗传学显示，p53 和 LKB1/STK11 是散发性人类非小细胞肺癌 (NSCLC) 中最常见的突变肿瘤抑制因子，而散发性人类非小细胞肺癌 (NSCLC) 是美国每年癌症死亡的主要来源。LKB1/STK11编码 Ser/Thr 蛋白激酶，可直接磷酸化 AMP 激活蛋白激酶 (AMPK) 的激活环，以及 12 种鲜为人知的相关激酶AMPK 家族。 AMPK 是细胞和有机体代谢的主要调节因子，充当细胞能量传感器，在 ATP 水平较低时阻止细胞生长并重新编程代谢。在过去的 5 年里，包括我们在内的许多实验室已经解码了 AMPK 和相关激酶的底物，这些激酶介导对生长和代谢的下游影响，并且可能与 LKB1 的肿瘤抑制活性有关，包括哺乳动物靶标中核心成分的 AMPK 磷酸化。雷帕霉素 (mTOR) 和自噬途径。此外，一线 2 型糖尿病药物二甲双胍已被证明在某些情况下能够以 AMPK 和 mTOR 依赖性方式调节细胞生长，这表明它可以作为潜在的抗癌药物。尽管 AMPK 和生长调节剂之间存在这些直接联系，但 AMPK 及其 12 种相关激酶的下游功能和效应器之间存在大量重叠，因此目前尚不清楚 LKB1 直接激活的这 14 种激酶中哪一种对于介导最关键其抑癌作用。此外，越来越多的证据表明，在许多情况下，AMPK 在葡萄糖或缺氧条件下恢复代谢稳态的能力可能会促进癌细胞的存活。因此，AMPK 在肿瘤发生中的作用可能非常依赖于背景，并且不同的 AMPK 相关激酶可能对于 LKB1 抑制 NSCLC 的能力更为重要。最后，虽然流行病学数据和小鼠异种移植物和烟草致癌物模型支持二甲双胍的有益作用，但尚未在人类癌症的基因工程小鼠模型中以允许区分基因型特异性治疗效果的方式进行检查。此外，二甲双胍及其更有效的类似物苯乙双胍是线粒体抑制剂，影响 AMPK 之外的途径，并且可以选择性地杀死 LKB1 缺陷的肿瘤，正如在细胞培养模型中观察到的那样。具体目标是 1) 确定 14 种 AMPK 家族激酶中的哪一种对于 LKB1 在 NSCLC 异种移植模型中抑制肿瘤发生的能力至关重要； 2) 从基因角度定义 AMPKa1 或 AMPKa2 及相关家族激酶在 NSCLC 基因工程小鼠模型中的作用； 3) 检查 AMPK 激活双胍化合物二甲双胍和苯乙双胍在多种 NSCLC 基因工程小鼠模型中的治疗效果和基因型选择性。