Deciphering the Role of Reductive Stress in Non Small Cell Lung Cancer
解读还原应激在非小细胞肺癌中的作用
基本信息
- 批准号:10365388
- 负责人:
- 金额:$ 38.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-13 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:AntioxidantsApplications GrantsAspartateBiochemicalBiologic CharacteristicBiological AssayBiological MarkersBiologyCRISPR screenCancer ModelCancer PatientCancer cell lineCell ProliferationCellsChemicalsCompanionsComplexCysteineDependenceDrug Metabolic DetoxicationElectron TransportEnvironmentEnzymesEquilibriumFoundationsFunctional disorderGene DeletionGenerationsGenesGeneticGenetic TranscriptionGenomicsGoalsGrowthHomeostasisImpairmentIn VitroLeadMaintenanceMalignant NeoplasmsMalignant neoplasm of lungMeasuresMediatingMetabolicMetabolic PathwayMetabolismMethodsMitochondriaModelingModificationMutationNon-Small-Cell Lung CarcinomaOncogenicOxidation-ReductionOxidative StressOxidesPathway interactionsPatientsPharmacologyPlayPoint MutationProductionProteinsProteomicsReactive Oxygen SpeciesRegulationResearchRespirationRoleSeriesSignal TransductionSignal Transduction PathwaySignaling ProteinStressSupplementationTechnologyTestingTherapeuticTumor Suppressor ProteinsWorkanti-cancer therapeuticbasecancer cellcancer therapycancer typecell growthcohortefficacy testingexperimental studyfunctional genomicsgenome-widein vivoinsightlung cancer cellmetabolomicsmitochondrial metabolismmutantnext generationnovelnovel therapeutic interventionpotential biomarkerprotein functionreconstitutionresponsesmall molecule inhibitorstress reductiontherapeutic developmenttherapeutic evaluationtranscription factortranscriptomicstranslational therapeuticstumor growth
项目摘要
Project Summary
Control of the redox homeostasis is essential to cancer cell proliferation and requires the delicate maintenance
of oxidative and reductive metabolic pathways. This equilibrium is controlled by signal transduction pathways
and imbalances lead to redox stress that potently blocks cancer growth. Much work has focused on the role of
oxidative stress in cancer proliferation, however, the converse– reductive stress and its impact on malignant
cells is poorly understood. We have studied the role of redox control in cancer in the context of modification of
proteinaceous cysteines by reactive oxygen species and the NRF2 transcription factor pathway. NRF2 functions
as the master regulator of the cellular antioxidant response and promotes the expression of key metabolic and
detoxification genes to generate a reductive environment and negate oxidative stress. NRF2 is activated in many
cancers including ~30% of non small cell lung cancers (NSCLC) through mutation of its negative regulator
KEAP1. While NRF2 has been extensively studied in KEAP1-mutant NSCLCs, we wondered what role this
pathway plays in the proliferation of NSCLC cell lines which are wildtype (WT) for KEAP1. To this end, we
pharmacologically activated NRF2 in 50+ NSCLC cell lines (WT for KEAP1) and measured their proliferation.
Unexpectedly, we find that in ~16% of NSCLC cell lines, NRF2 activation results in a severe block in proliferation.
A genome wide CRISPR screen identifies that genes involved in mitochondrial metabolism, mitochondrial fusion
and the electron transport chain (ETC) are major sensitizers to NRF2 activation when lost and can function as
companion biomarkers for NRF2-sensitivity. In line with the generation of reductive stress following NRF2
activation, key cysteines on enzymes involved in mitochondrial metabolism and mitochondrial fusion are reduced
as determined by chemical proteomic platforms. To explain these surprising biological characteristics we
propose the following hypothesis: NRF2 activation in a subset of NSCLC cell lines promotes an overly reductive
environment that decreases the activity of key enzymes in mitochondrial metabolism and mitochondrial
respiration and fusion. The inactivation of these pathways synergize to block cell growth. In this grant application,
we build on our research surrounding NRF2 sensitization and mechanistically characterize the role of reductive
stress in NSCLC proliferation. In this grant application, we will comprehensively define KEAP1-dependence by
identifying NRF2 regulation of mitochondrial metabolism/fusion at the protein, cellular and organismal levels.
The research proposed herein, takes full advantage of a series of recently conceived methods: chemical
proteomics, genome-wide CRISPR screens and untargeted metabolomics, which have previously been
deployed in isolation, to be used in an integrated manner to effectively dissect how protein reduction underlies
protein malfunction and KEAP1-dependence. These studies will not only provide a comprehensive
understanding of NRF2/KEAP1 biology but may also lay the foundation for developing translational therapeutics
to benefit lung cancer patients with deregulated NRF2 signaling.
项目概要
氧化还原稳态的控制对于癌细胞增殖至关重要,需要精心维护
氧化和还原代谢途径的平衡由信号转导途径控制。
不平衡会导致氧化还原应激,从而有效阻止癌症生长。
癌症增殖中的氧化应激,然而,相反的还原应激及其对恶性的影响
我们对氧化还原控制在癌症中的作用了解甚少。
蛋白质半胱氨酸通过活性氧和 NRF2 转录因子途径发挥作用。
作为细胞抗氧化反应的主要调节剂,促进关键代谢和
产生还原环境并消除氧化应激的解毒基因在许多细胞中被激活。
通过其负调节因子的突变导致癌症,包括约 30% 的非小细胞肺癌 (NSCLC)
虽然 NRF2 在 KEAP1 突变 NSCLC 中得到了广泛研究,但我们想知道它的作用是什么。
通路在 KEAP1 野生型 (WT) NSCLC 细胞系的增殖中发挥作用。
在 50 多个 NSCLC 细胞系(KEAP1 的 WT)中药理学激活 NRF2 并测量其增殖。
出乎意料的是,我们发现在约 16% 的 NSCLC 细胞系中,NRF2 激活会导致增殖严重受阻。
全基因组 CRISPR 筛选鉴定出参与线粒体代谢、线粒体融合的基因
电子传递链 (ETC) 是 NRF2 丢失时激活的主要敏化剂,可充当
NRF2 敏感性的伴随生物标志物 与 NRF2 后还原应激的产生一致。
激活,参与线粒体代谢和线粒体融合的酶上的关键半胱氨酸减少
为了解释这些令人惊讶的生物学特征,我们通过化学蛋白质组学平台确定。
提出以下假设:NSCLC 细胞系子集中的 NRF2 激活促进过度还原
降低线粒体代谢和线粒体中关键酶活性的环境
呼吸和融合的失活协同作用阻止细胞生长。
我们以围绕 NRF2 敏化的研究为基础,并机械地表征了还原的作用
在本次拨款申请中,我们将通过以下方式全面定义 KEAP1 依赖性。
NRF2 在蛋白质、细胞和生物水平上调节线粒体代谢/融合。
本文提出的研究充分利用了一系列最近构思的方法:化学
蛋白质组学、全基因组 CRISPR 筛选和非靶向代谢组学
单独部署,以综合方式使用,以有效剖析蛋白质减少的基础
这些研究不仅会提供全面的蛋白质功能障碍和KEAP1依赖性。
了解 NRF2/KEAP1 生物学,但也可能为开发转化疗法奠定基础
使 NRF2 信号传导失调的肺癌患者受益。
项目成果
期刊论文数量(0)
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{{ truncateString('Liron Bar-Peled', 18)}}的其他基金
Defining Nuclear H2O2 Regulation by Covalent Regulators
通过共价调节剂定义核 H2O2 调节
- 批准号:
10725269 - 财政年份:2023
- 资助金额:
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Chemical Proteomic Identification of Druggable Oncogenic Transcription Factors
可药物致癌转录因子的化学蛋白质组学鉴定
- 批准号:
10357900 - 财政年份:2021
- 资助金额:
$ 38.43万 - 项目类别:
Deciphering the Role of Reductive Stress in Non Small Cell Lung Cancer
解读还原应激在非小细胞肺癌中的作用
- 批准号:
10540372 - 财政年份:2021
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Chemical Proteomic Identification of Druggable Oncogenic Transcription Factors
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- 批准号:
10113070 - 财政年份:2021
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$ 38.43万 - 项目类别:
Chemical Proteomic Identification of Druggable Oncogenic Transcription Factors
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10576274 - 财政年份:2021
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$ 38.43万 - 项目类别:
Mapping druggable co-dependency pathways in NRF2-driven lung cancers
绘制 NRF2 驱动的肺癌的药物共依赖性途径
- 批准号:
9891966 - 财政年份:2017
- 资助金额:
$ 38.43万 - 项目类别:
Mapping druggable co-dependency pathways in NRF2-driven lung cancers
绘制 NRF2 驱动的肺癌的药物共依赖性途径
- 批准号:
9294607 - 财政年份:2017
- 资助金额:
$ 38.43万 - 项目类别:
Mapping druggable co-dependency pathways in NRF2-driven lung cancers
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- 批准号:
10115633 - 财政年份:2017
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