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: 8785659
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785659
• 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; Cells; Cessation of life; Data; Development; Diabetes Mellitus; Environment; Epidemiologic Studies; Epidemiology; Epithelial Cells; Exhibits; 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; 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; mTOR protein; mouse model; novel therapeutics; preclinical study; 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.

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激酶（AMPK）以及AMPK家族中相关的12个相关激酶。 AMPK是细胞和有机代谢的主要调节剂，它充当细胞能的传感器，在ATP水平较低时会阻止细胞生长和重编代谢。在过去的5年中，包括我们的许多实验室已经解码了AMPK的底物和相关的激酶，它们介导了下游对生长和代谢的影响，并且可能与LKB1的肿瘤抑制活性有关，包括AMPK磷酸化的乳腺癌（MTOR）和自动型疗法的乳腺癌靶标的核心成分和核心成分。此外，在某些情况下，前线2型糖尿病药物二甲双胍已被证明可以以AMPK和MTOR依赖性方式调节细胞生长，这表明它可能是潜在的抗癌剂。尽管AMPK与增长调节剂之间存在这些直接连接，但AMPK的下游功能与效应子及其12种相关激酶之间存在很大的重叠，因此尚不清楚LKB1直接激活的14种激酶中的哪种是介导其肿瘤抑制功能的最重要的。此外，积累的证据表明，在许多情况下，AMPK在葡萄糖或贫血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上下文，并且不同AMPK相关的激酶对于LKB1抑制NSCLC的能力可能更为重要。最后，尽管流行病学数据以及小鼠异种移植物和烟草致癌模型支持二甲双胍的有益作用，但尚未在人类癌的基因工程小鼠模型中进行检查，以区分基因型特异性治疗效应。此外，二甲双胍及其更有效的模拟苯甲甲是影响AMPK之外途径的线粒体抑制剂，并且可以选择性地允许杀死LKB1缺陷型肿瘤，如细胞培养模型所观察到的那样。具体目的是1）定义14个AMPK家族激酶中的哪种对于LKB1在NSCLC异种移植模型中抑制肿瘤发生的能力至关重要； 2）遗传定义AMPKA1或AMPKA2和相关家族激酶在NSCLC的基因工程小鼠模型中的作用； 3）检查了NSCLC多种基因工程小鼠模型中，AMPK激活Biguanide化合物的二甲甲酰胺化合物的治疗功效和基因型选择性。