Investigating the glycolytic interactome to understand cancer metabolism

研究糖酵解相互作用组以了解癌症代谢

• 批准号: 8525561
• 负责人: William Comb
• 金额: $ 1.42万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525561
• 关键词: Biochemical; Biochemical Pathway; Biological; Catabolism; Cell Proliferation; Cells; Characteristics; Clinical; Complex; Enzyme Interaction; Enzymes; Evolution; Fermentation; Glucose; Glycolysis; Goals; Growth; Human; Investigation; Knowledge; Label; Lactic acid; Malignant - descriptor; Malignant Neoplasms; Mammalian Cell; Mediating; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Mission; Molecular; Normal tissue morphology; Nucleic Acid Regulatory Sequences; Organism; Oxygen; Pathway interactions; Peptides; Physiological; Proliferating; Protein Region; Proteins; Proteomics; RNA Interference; Regulation; Role; Structure; Techniques; Technology; Therapeutic; United States National Institutes of Health; Warburg Effect; aerobic glycolysis; base; cancer cell; cell growth; cell transformation; design; genetic regulatory protein; glucose metabolism; glucose uptake; inhibitor/antagonist; insight; loss of function; malignant breast neoplasm; malignant phenotype; metabolomics; mutant; neoplastic cell; novel; novel strategies; programs; protein protein interaction; public health relevance; screening; tool; tumor; tumor metabolism; tumorigenesis

DESCRIPTION (provided by applicant): Cancer cells, compared to normal tissue, display increased glucose uptake and metabolism via aerobic glycolysis, even in the presence of ample oxygen. This observation, termed the Warburg Effect, was paradoxical because it meant that cancer cells used a seemingly less efficient metabolic pathway to convert glucose to energy in the form of ATP. More recent investigations have demonstrated that glycolytic intermediates serve as precursors for biosynthetic pathways necessary to support cellular proliferation. The observation that cancer cells preferentially use glycolysis has led many to explore metabolism as a novel window of therapeutic opportunity for a number of tumors. Herein we propose a systematic and unbiased approach to identify glycolytic interacting proteins (GIPs) in order to better understand regulation of glycolysis in cancer. We hypothesize that glycolytic regulation in cancer cells occurs through interactions between GIPS and glycolytic enzymes and that these interactions contribute to the malignant phenotype of cancer cells. Using SILAC-based proteomics we have identified interactions enriched in cells with increased Warburg Effect, which has generated the hypothesis that increased interactions with GIPs drive glycolysis in the transformed state. We will determine which GIPs are essential for proliferation and viability using pooled RNAi screening technologies. Structural approaches will be applied to gain insights toward GIP regulatory function and this information will be used to generate tools to disrupt these potentially important interactions. Finally we will examine how transformation and the glycolytic protein interactome contribute to the overall metabolic program of the cell. The aims presented in this proposal will greatly expand our knowledge of cancer metabolism and are thus directly relevant to the mission of the National Institutes of Health.

描述（由申请人提供）：与正常组织相比，癌细胞显示出增加的葡萄糖摄取和通过有氧糖酵解的代谢，即使在充足氧气的存在下。这一观察结果被称为瓦尔堡效应，它是自相矛盾的，因为它意味着癌细胞使用一种看似效率较低的代谢途径将葡萄糖转化为ATP形式的能量。最近的研究表明，糖酵解中间体作为支持细胞增殖所必需的生物合成途径的前体。癌细胞优先利用糖酵解的观察结果导致许多人探索代谢作为许多肿瘤治疗机会的新窗口。在此，我们提出了一个系统的和公正的方法来确定糖酵解相互作用蛋白（GIP），以更好地了解调节糖酵解在癌症中。我们推测，糖酵解调节癌细胞发生通过GIPS和糖酵解酶之间的相互作用，这些相互作用有助于癌细胞的恶性表型。使用基于SILAC的蛋白质组学，我们已经鉴定了在具有增加的瓦尔堡效应的细胞中富集的相互作用，这产生了与GIP的增加的相互作用驱动转化状态下的糖酵解的假设。我们将使用合并的RNAi筛选技术来确定哪些GIP对于增殖和活力是必不可少的。结构方法将被应用于获得对GIP调节功能的见解，这些信息将被用来生成工具来破坏这些潜在的重要相互作用。最后，我们将研究如何转化和糖酵解蛋白相互作用体有助于细胞的整体代谢程序。本提案中提出的目标将大大扩展我们对癌症代谢的认识，因此与国立卫生研究院的使命直接相关。