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
基本信息
- 批准号:9186506
- 负责人:
- 金额:$ 40.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:5&apos-AMP-activated protein kinaseAffectAnimal ModelAntibodiesAntineoplastic AgentsApoptosisAutophagocytosisBiguanidesBiochemical PathwayBiological AvailabilityCancer EtiologyCancer ModelCancer cell lineCell Culture TechniquesCell DeathCell PolarityCell SurvivalCellular Metabolic ProcessCessation of lifeDevelopmentDiabetes MellitusEnterobacteria phage P1 Cre recombinaseEnvironmentEpithelial CellsExhibitsFRAP1 geneFamilyFamily memberGenesGeneticGenetic EngineeringGenetically Engineered MouseGenotypeGlucoseGrowthHeadHomeostasisHumanImmunocompromised HostIndividualKRP proteinLungLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMediatingMetabolicMetabolismMetforminMitochondriaModelingMusMutateMutationNon-Insulin-Dependent Diabetes MellitusNon-Small-Cell Lung CarcinomaNutrientOxygenPathway interactionsPharmaceutical PreparationsPhenforminPhosphorylationPhosphotransferasesPhysiologicalPropertyProtein IsoformsProtein KinaseProteinsResearchRoleSTK11 geneSerineSignal PathwaySourceStressSubfamily lentivirinaeTP53 geneTestingTherapeuticTherapeutic EffectThreonineTimeTissuesTobacco-Associated CarcinogenTreatment EfficacyTumor SuppressionTumor Suppressor ProteinsXenograft ModelXenograft procedureanalogcancer cellcancer geneticscancer survivalcell growthepidemiologic dataepidemiology studyin vivoinhibitor/antagonistinterestkillingsmouse modelnon-geneticnovel therapeuticspreclinical studypreclinical trialpublic health relevancesensorsmall hairpin RNAtherapeutic targettumortumor initiationtumor xenografttumorigenesis
项目摘要
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(申请人提供):癌症遗传学已经揭示,p53和LKB 1/STK 11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,LKB 1/STK 11编码一种Ser/Thr蛋白激酶,可直接磷酸化AMP活化蛋白激酶(AMPK)的活化环以及AMPK家族中12种知之甚少的相关激酶。AMPK是细胞和有机体代谢的主要调节剂,其充当细胞能量的传感器,在ATP水平低时阻止细胞生长和重编程代谢。在过去的5年中,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,并可能与LKB 1的肿瘤抑制活性有关,包括哺乳动物雷帕霉素靶蛋白(mTOR)和自噬途径中核心组分的AMPK磷酸化。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以AMPK和mTOR依赖性方式调节细胞生长,这表明它可能作为一种潜在的抗癌药物。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子之间存在大量重叠,因此仍不清楚LKB 1直接激活的这14种激酶中哪一种对于介导其肿瘤抑制功能最关键。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环境,不同的AMPK相关激酶可能对LKB 1抑制NSCLC的能力更重要。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作用的方式对其进行检查。此外,二甲双胍及其更有效的类似物苯丙氨酸是线粒体抑制剂,影响AMPK以外的途径,并可能选择性地允许杀死LKB 1缺陷型肿瘤,如在细胞培养模型中观察到的。具体目的是1)确定14种AMPK家族激酶中的哪些对于LKB 1在NSCLC异种移植模型中抑制肿瘤发生的能力是必需的; 2)从遗传学上确定AMPKa 1或AMPKa 2和相关家族激酶在NSCLC基因工程小鼠模型中的作用;和3)检查AMPK-1的治疗功效和基因型选择性。在NSCLC的多种基因工程小鼠模型中激活双胍化合物二甲双胍和苯丙氨酸。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Reuben Shaw其他文献
Reuben Shaw的其他文献
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{{ truncateString('Reuben Shaw', 18)}}的其他基金
Project 3: The AMPK Autophagy Pathway as a Metabolic Liability in Pancratic Ductal Adenocarcinoma
项目 3:AMPK 自噬途径作为胰腺导管腺癌的代谢负担
- 批准号:
10629065 - 财政年份:2023
- 资助金额:
$ 40.26万 - 项目类别:
Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer
解码并靶向癌症中的 LKB1-AMPK 信号通路
- 批准号:
10667573 - 财政年份:2017
- 资助金额:
$ 40.26万 - 项目类别:
Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer
解码并靶向癌症中的 LKB1-AMPK 信号通路
- 批准号:
10448279 - 财政年份:2017
- 资助金额:
$ 40.26万 - 项目类别:
Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer
解码并靶向癌症中的 LKB1-AMPK 信号通路
- 批准号:
10222594 - 财政年份:2017
- 资助金额:
$ 40.26万 - 项目类别:
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:
8605862 - 财政年份:2013
- 资助金额:
$ 40.26万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 40.26万 - 项目类别:
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:
8420203 - 财政年份:2013
- 资助金额:
$ 40.26万 - 项目类别:
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
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Role of LKB1 and AMPK in Metformin and TZD Control of Glucose Metabolism in Liver
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