Role of Glutaminolysis in the Myc-induced Metabolic Phenotype of Tumor Cells

谷氨酰胺分解在 Myc 诱导的肿瘤细胞代谢表型中的作用

基本信息

  • 批准号:
    8191915
  • 负责人:
  • 金额:
    $ 13.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-07-05 至 2013-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Reprogramming of glucose and glutamine metabolism is a key event in malignant transformation. However, the functional drivers and molecular pathways underlying these adaptations are only now starting to emerge. Our long-term goal is to understand mechanisms of metabolic reprogramming in tumor cells so that these processes can be targeted by molecular cancer therapeutics. The overall objective of the current application is to apply systems approaches to elucidate the functional role of the glutaminolytic phenotype elicited by overexpression of the Myc oncoprotein. Myc is an important regulator of both aerobic glycolysis as well as glutaminolysis in tumor cells, the latter of which is characterized by avid consumption of the non-essential amino acid glutamine. Our central hypothesis is that the glutaminolytic phenotype induced by Myc overexpression is important for combating oxidative stress and fueling lipid synthesis in rapidly dividing cells. The rationale for the proposed research is that, once we have identified the functional significance of Myc- induced metabolic reprogramming, these processes can be targeted to undermine the advantages they confer on tumor cells. We plan to test our central hypothesis by pursuing the following specific aims: (1) to determine the role of glutaminolysis in detoxification of reactive oxygen species and (2) to determine the role of glutaminolysis in promoting lipid synthesis. The proposed research is innovative because it applies systems approaches to quantitatively elucidate the global behavior of integrated metabolic networks, rather than individual reactions or nodes in isolation. We will apply metabolic flux analysis (MFA) to quantify metabolic phenotypes in P493-6 Burkitt's lymphoma cells as well as mouse embryonic fibroblasts that are dependent on Myc for their malignant transformation. These cells contain Myc constructs that can be modulated to achieve tuned levels of overexpression. The cells will be subjected to different treatments intended to elucidate the role of glycolysis and glutaminolysis in both cellular redox balancing and anaplerotic processes. In particular, we will simultaneously quantify flux through all three major routes of cytosolic NADPH production, which are important for maintenance of redox homeostasis in proliferating cells. Furthermore, we will investigate the regulation of pathways that serve to convert glucose and glutamine into lipid intermediates required to support cell growth. As a result of this work, we expect to contribute a deeper understanding of how Myc regulates cellular metabolism and how these adaptations provide a growth advantage to tumor cells. This is significant because it will stimulate the search for novel drug targets that can inhibit the progression of Myc-dependent tumors. This work will also provide an avenue toward personalized medicine by identifying the unique metabolic signatures of Myc overexpression. PUBLIC HEALTH RELEVANCE: The proposed research will have an important positive impact in the search for novel drug targets for cancer therapy. In addition, it will provide fundamental insights into the nature of metabolic reprogramming in cancer cells and how these events contribute to malignancy. Because direct inhibitors of Myc are not currently available to clinicians, reversal of Myc-induced metabolic phenotypes may provide a surrogate strategy to suppress the growth of Myc-dependent tumors.
描述(由申请人提供):葡萄糖和谷氨酰胺代谢的重编程是恶性转化的关键事件。然而,这些适应背后的功能驱动因素和分子途径现在才刚刚开始出现。我们的长期目标是了解肿瘤细胞代谢重编程的机制,以便分子癌症疗法能够针对这些过程。本申请的总体目标是应用系统方法来阐明 Myc 癌蛋白过度表达引起的谷氨酰胺分解表型的功能作用。 Myc 是肿瘤细胞中有氧糖酵解和谷氨酰胺分解的重要调节剂,后者的特点是大量消耗非必需氨基酸谷氨酰胺。我们的中心假设是,Myc 过度表达诱导的谷氨酰胺分解表型对于对抗氧化应激和促进快速分裂细胞中的脂质合成非常重要。这项研究的基本原理是,一旦我们确定了 Myc 诱导的代谢重编程的功能意义,就可以针对这些过程来破坏它们赋予肿瘤细胞的优势。我们计划通过追求以下具体目标来检验我们的中心假设:(1)确定谷氨酰胺分解在活性氧解毒中的作用;(2)确定谷氨酰胺分解在促进脂质合成中的作用。拟议的研究具有创新性,因为它应用系统方法来定量阐明综合代谢网络的全局行为,而不是孤立的单个反应或节点。我们将应用代谢流分析 (MFA) 来量化 P493-6 Burkitt 淋巴瘤细胞以及依赖 Myc 进行恶性转化的小鼠胚胎成纤维细胞的代谢表型。这些细胞含有 Myc 构建体,可以对其进行调节以实现调整的过度表达水平。这些细胞将接受不同的处理,旨在阐明糖酵解和谷氨酰胺分解在细胞氧化还原平衡和回补过程中的作用。特别是,我们将同时量化胞质 NADPH 产生的所有三种主要途径的通量,这对于维持增殖细胞中的氧化还原稳态非常重要。此外,我们将研究将葡萄糖和谷氨酰胺转化为支持细胞生长所需的脂质中间体的途径的调节。通过这项工作,我们希望能够更深入地了解 Myc 如何调节细胞代谢以及这些适应如何为肿瘤细胞提供生长优势。这很重要,因为它将刺激寻找能够抑制 Myc 依赖性肿瘤进展的新药物靶点。这项工作还将通过识别 Myc 过度表达的独特代谢特征,为个性化医疗提供一条途径。 公共健康相关性:拟议的研究将对寻找癌症治疗的新药物靶点产生重要的积极影响。此外,它将提供关于癌细胞代谢重编程的性质以及这些事件如何导致恶性肿瘤的基本见解。由于临床医生目前无法获得 Myc 的直接抑制剂,因此逆转 Myc 诱导的代谢表型可能提供一种替代策略来抑制 Myc 依赖性肿瘤的生长。

项目成果

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Jamey D. Young其他文献

Applications of stable isotope‐based metabolomics and fluxomics toward synthetic biology of cyanobacteria
基于稳定同位素的代谢组学和通量组学在蓝藻合成生物学中的应用
Hypoxia uncouples HIF gene transcription and metabolic flux in proliferating primary cells
缺氧使增殖原代细胞中的 HIF 基因转录和代谢通量解耦
  • DOI:
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Courtney A. Copeland;B. Olenchock;Jamey D. Young;J. Loscalzo;W. Oldham
  • 通讯作者:
    W. Oldham
Analyzing the Efficacy of Different Gas Chromatography-Mass Spectrometry Methods in Determining Glucose Concentrations
分析不同气相色谱-质谱法测定葡萄糖浓度的功效
  • DOI:
    10.2337/dbi18-0055
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    A. Oates;Mohsin Rahim;Jamey D. Young
  • 通讯作者:
    Jamey D. Young
Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection
宿主营养环境在侵袭性金黄色葡萄球菌感染期间对天冬氨酸生物合成发挥重要作用
Comparative analysis of cyanobacteria species reveals a novel guanidine-degrading enzyme that controls genomic stability of ethylene-producing strains
蓝藻物种的比较分析揭示了一种新型胍降解酶,可控制乙烯产生菌株的基因组稳定性
  • DOI:
    10.21203/rs.3.rs-197190/v1
  • 发表时间:
    2021-03-29
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bo Wang;Yao Xu;Xin Wang;Joshua S. Yuan;C. Johnson;Jamey D. Young;Jianping Yu
  • 通讯作者:
    Jianping Yu

Jamey D. Young的其他文献

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{{ truncateString('Jamey D. Young', 18)}}的其他基金

Integrated multi-tissue 13C flux analysis platform to assess renal metabolism in vivo
用于评估体内肾脏代谢的集成多组织 13C 通量分析平台
  • 批准号:
    10727785
  • 财政年份:
    2023
  • 资助金额:
    $ 13.04万
  • 项目类别:
In Vivo 2H/13C Metabolic Flux Analysis of NASH Pathogenesis
NASH 发病机制的体内 2H/13C 代谢通量分析
  • 批准号:
    9276004
  • 财政年份:
    2015
  • 资助金额:
    $ 13.04万
  • 项目类别:
In Vivo 2H/13C Metabolic Flux Analysis of NASH Pathogenesis
NASH 发病机制的体内 2H/13C 代谢通量分析
  • 批准号:
    8946823
  • 财政年份:
    2015
  • 资助金额:
    $ 13.04万
  • 项目类别:
Integrated Training in Engineering and Diabetes
工程和糖尿病综合培训
  • 批准号:
    10660970
  • 财政年份:
    2014
  • 资助金额:
    $ 13.04万
  • 项目类别:
Integrated Training in Engineering and Diabetes
工程和糖尿病综合培训
  • 批准号:
    10220020
  • 财政年份:
    2014
  • 资助金额:
    $ 13.04万
  • 项目类别:
Integrated Training in Engineering and Diabetes
工程和糖尿病综合培训
  • 批准号:
    10457263
  • 财政年份:
    2014
  • 资助金额:
    $ 13.04万
  • 项目类别:
Integrated Training in Engineering and Diabetes
工程和糖尿病综合培训
  • 批准号:
    10452921
  • 财政年份:
    2014
  • 资助金额:
    $ 13.04万
  • 项目类别:
Integrated Training in Engineering and Diabetes
工程和糖尿病综合培训
  • 批准号:
    10173164
  • 财政年份:
    2014
  • 资助金额:
    $ 13.04万
  • 项目类别:
Role of Glutaminolysis in the Myc-induced Metabolic Phenotype of Tumor Cells
谷氨酰胺分解在 Myc 诱导的肿瘤细胞代谢表型中的作用
  • 批准号:
    8296584
  • 财政年份:
    2011
  • 资助金额:
    $ 13.04万
  • 项目类别:
Nonstationary Isotopic Tracer Analysis of Hepatocytes
肝细胞的非稳态同位素示踪分析
  • 批准号:
    6999604
  • 财政年份:
    2005
  • 资助金额:
    $ 13.04万
  • 项目类别:

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