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.

项目总结/摘要 营养素和代谢物可以积极和消极地调节细胞信号传导，合成代谢， 影响癌症的生长。一种促进癌症生长的营养素是天冬酰胺， 癌细胞可以从微环境中摄取，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点：L- 天冬酰胺酶是一种标准的治疗急性淋巴细胞白血病的药物， 白血病毫不奇怪，白血病对天冬酰胺酶的耐药性与ASNS活性增加有关， 生物合成我们最近报道了细胞内天冬酰胺水平限制癌细胞增殖 并且天冬酰胺被癌细胞用作氨基酸交换因子， 微环境。天冬酰胺的这种交换功能使mTORC 1活化， 促进合成代谢。我们的初步数据进一步表明，mTORC 1，增加 糖酵解沿着合成代谢，可能会受到乳酸（糖酵解的最终产物）的反馈抑制 糖酵解乳酸通过单羧酸转运蛋白从癌细胞中大量输出 （MCT），并且阻断乳酸输出减少肿瘤生长。为什么癌细胞会输出这么多乳酸？ 乳酸能否提供一个负反馈信号来抑制体内平衡状态下的进一步抑制？做 通常表达相对高水平MCT的癌细胞逃避这种负反馈机制 通过乳酸盐出口 这项建议将调查的机制，促进生长的信号通路都积极 并受代谢物的负调节，并探索使用 现有临床化合物的合理组合。具体来说，我们将：（1）确定呼吸是否 通过天冬酰胺的产生支持癌细胞增殖;（2）评估合理的联合治疗 使用L-天冬酰胺酶的策略，利用癌细胞对天冬酰胺的依赖性进行生长;和（3）检查 乳酸调节mTORC 1和转录激活因子4活性。阐明营养调控 癌症生长将促进更好的癌症治疗策略的发展， 抵抗的机会有限。