Nutrient regulation of cancer cell growth

癌细胞生长的营养调节

• 批准号: 10304890
• 负责人: Heather Christofk
• 金额: $ 34.3万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-06 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304890
• 关键词: Acute Lymphocytic Leukemia; Affect; Affinity; Amino Acids; Anabolism; Asparagine; Aspartate; Aspartate-Ammonia Ligase; Binding; Binding Sites; Breast Cancer Cell; CRISPR/Cas technology; Cancer Cell Growth Regulation; Cancer cell line; Carbon; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cells; Clinical; Co-Immunoprecipitations; Complex; Consumption; Data; Dependence; Development; Electron Transport; Essential Amino Acids; Event; FRAP1 gene; Feedback; Glutamate-Ammonia Ligase; Glutaminase; Glutamine; Glycolysis; Growth; Guanine Nucleotide Exchange Factors; Homeostasis; In Vitro; Knock-out; Lymphoblastic Leukemia; Malignant Neoplasms; Metabolism; Metformin; Mus; Nitrogen; Nutrient; Phenylbutyrates; Production; Protein Truncation; Radiolabeled; Reaction; Regulation; Reporting; Resistance; Respiration; Serine; Signal Pathway; Signal Transduction; Testing; Translating; Xenograft Model; activating transcription factor 4; asparaginase; cancer cell; cancer therapy; design; experimental study; extracellular; inhibitor; leukemia; nucleotide metabolism; prevent; standard of care; therapeutic target; treatment strategy; tumor; tumor growth; tumor xenograft; uptake

PROJECT SUMMARY/ABSTRACT Nutrients and metabolites can both positively and negatively regulate cell signaling, anabolic metabolism, and proliferation to impact cancer growth. One nutrient that promotes cancer growth is asparagine, an amino acid cancer cells can either take up from the microenvironment or synthesize through asparagine synthetase (ASNS) from glutamine and aspartate. Cancer cell asparagine consumption is already a therapeutic target: L- asparaginase, which digests extracellular asparagine, is a standard-of-care treatment for acute lymphoblastic leukemia. Not surprisingly, leukemic resistance to asparaginase is associated with increased ASNS activity for biosynthesis. We recently reported that intracellular asparagine levels are limiting for cancer cell proliferation and that asparagine is used by cancer cells as an amino acid exchange factor for uptake of amino acids from the microenvironment. This exchange function of asparagine enables mTORC1 activation and downstream promotion of anabolic metabolism. Our preliminary data further suggest that mTORC1, which increases glycolysis along with anabolic metabolism, may be subject to feedback inhibition by lactate, the end product of glycolysis. Lactate is exported in large amounts from cancer cells through monocarboxylate transporters (MCTs), and blocking lactate export reduces tumor growth. Why do cancer cells export so much lactate? Could lactate provide a negative feedback signal to inhibit further anabolism in homeostatic situations? Do cancer cells, which generally express relatively high levels of MCTs, evade this negative feedback mechanism through lactate export? This proposal will investigate mechanisms by which growth-promoting signaling pathways are both positively and negatively regulated by metabolites, and explore ways to therapeutically target this regulation using rational combinations of existing clinical compounds. Specifically, we will: (1) Determine whether respiration supports cancer cell proliferation through asparagine production; (2) Assess rational combination treatment strategies with L-asparaginase to exploit cancer cell dependence on asparagine for growth; and (3) Examine lactate regulation of mTORC1 and activating transcription factor 4 activities. Elucidating nutrient regulation of cancer growth will promote development of better cancer treatment strategies that block tumor growth with limited opportunity for resistance.

项目摘要/摘要 营养和代谢物既可以积极和负面调节细胞信号传导，合成代谢代谢和 扩散以影响癌症的生长。一种促进癌症生长的营养素是天冬酰胺，一种氨基酸 癌细胞可以从微环境中占用，也可以通过天冬酰胺合成酶合成 （ASNS）来自谷氨酰胺和天冬氨酸。癌细胞天冬酰胺消耗已经是一个治疗靶标：l- 消化细胞外天冬酰胺的天冬酰胺酶是一种急性淋巴细胞标准治疗 白血病。毫不奇怪，白血病对天冬酰胺酶的抗性与ASNS活性的增加有关 生物合成。我们最近报道说，细胞内天冬酰胺水平限制了癌细胞增殖 癌细胞将天冬酰胺用作氨基酸交换因子，以吸收从 微环境。天冬酰胺的这种交换功能启用MTORC1激活和下游 促进代谢代谢。我们的初步数据进一步表明，MTORC1增加了 糖酵解以及合成代谢的代谢，可能会受到乳酸的反馈抑制，这是 糖酵解。乳酸通过单羧酸盐转运蛋白从癌细胞中大量出口 （MCT）并阻塞乳酸导出可减少肿瘤的生长。为什么癌细胞会出口这么多乳酸？ 乳酸可以提供负反馈信号以抑制稳态情况下进一步的合成代谢吗？做 癌细胞通常表达相对较高的MCT，逃避了这种负反馈机制 通过乳酸出口？ 该提案将调查促进生长信号通路的机制 并由代谢物负面调节，并探索使用治疗方法的方法 现有临床化合物的合理组合。具体来说，我们将：（1）确定是否呼吸 通过天冬酰胺的产生支持癌细胞增殖； （2）评估理性组合处理 具有L-天冬酰胺酶的策略来利用癌细胞依赖天冬酰胺的生长； （3）检查 MTORC1的乳酸调节和激活转录因子4活性。阐明的营养调节 癌症的增长将促进更好的癌症治疗策略，以阻止肿瘤生长 抵抗的机会有限。