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:8785659
- 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 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAMP-activated protein kinase kinaseAffectAnimal ModelAntibodiesAntineoplastic AgentsApoptosisAutophagocytosisBiguanidesBiochemical PathwayBiological AvailabilityCancer EtiologyCancer ModelCancer cell lineCell Culture TechniquesCell DeathCell PolarityCellsCessation of lifeDataDevelopmentDiabetes MellitusEnvironmentEpidemiologic StudiesEpidemiologyEpithelial CellsExhibitsFamilyFamily memberGenesGeneticGenetic EngineeringGenetically Engineered MouseGenotypeGlucoseGrowthHeadHomeostasisHumanImmunocompromised HostIndividualLungLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMediatingMetabolicMetabolismMetforminMitochondriaModelingMusMutateMutationNon-Insulin-Dependent Diabetes MellitusNon-Small-Cell Lung CarcinomaNutrientOxygenPathway interactionsPharmaceutical PreparationsPhenforminPhosphorylationPhosphotransferasesPhysiologicalPropertyProtein IsoformsProtein KinaseProteinsResearchRoleSTK11 geneSerineSignal PathwaySourceStressSubfamily lentivirinaeTestingTherapeuticTherapeutic EffectThreonineTimeTissuesTobacco-Associated CarcinogenTreatment EfficacyTumor SuppressionTumor Suppressor ProteinsXenograft ModelXenograft procedureanalogcancer cellcancer geneticscell growthin vivoinhibitor/antagonistinterestkillingsmTOR proteinmouse modelnovel therapeuticspreclinical studypublic health relevancerecombinasesensorsmall hairpin RNAtherapy developmenttumortumor 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):癌症遗传学已揭示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基因,NSCLC是美国每年癌症死亡的主要来源。LKB1/STK11编码一个丝氨酸/苏氨酸蛋白激酶(Ser/Thr),它直接磷酸化AMP激活蛋白激酶(AMPK)的激活环,以及AMPK家族中12种鲜为人知的相关激酶。AMPK是细胞和机体代谢的主要调节者,充当细胞能量的传感器,在ATP水平较低时阻止细胞生长和重新编程新陈代谢。在过去的5年里,包括我们在内的许多实验室已经破译了AMPK底物和相关的激酶,这些底物介导了对生长和代谢的下游影响,并可能与LKB1的肿瘤抑制活性有关,包括哺乳动物雷帕霉素靶标(MTOR)核心成分的AMPK磷酸化和自噬途径。此外,在某些情况下,一线的2型糖尿病药物二甲双胍被证明以AMPK和mTOR依赖的方式调节细胞生长,这表明它可能是一种潜在的抗癌药物。尽管AMPK和生长调节剂之间有这些直接联系,但AMPK及其12个相关激酶的下游功能和效应器之间存在很大的重叠,因此尚不清楚LKB1直接激活的14个激酶中,哪些是调节其肿瘤抑制功能最关键的。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上下文,而不同的AMPK相关激酶可能对LKB1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和烟草致癌物模型支持二甲双胍的有益效果,但这还没有在人类癌症的基因工程小鼠模型中以一种能够区分基因特异性治疗效果的方式进行检验。此外,二甲双胍及其更有效的类似物苯福明是线粒体抑制剂,可以影响AMPK以外的途径,并可能选择性地允许杀死LKB1缺陷的肿瘤,正如在细胞培养模型中观察到的那样。其具体目的是1)确定14个AMPK家族中的哪些对于LKB1在非小细胞肺癌异种移植模型中抑制肿瘤形成的能力是必不可少的;2)从遗传学角度确定AMPKa1或AMPKa2及相关家族激酶在非小细胞肺癌基因工程小鼠模型中的作用;以及3)检测AMPK激活双胍化合物二甲双胍和苯福明在多个非小细胞肺癌基因工程小鼠模型中的治疗效果和基因选择性。
项目成果
期刊论文数量(0)
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
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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
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9186506 - 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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