Fatty acid synthase in regulation of UDP-GlcNAc synthesis in colorectal cancer

脂肪酸合酶在结直肠癌中调节 UDP-GlcNAc 合成

• 批准号: 10437880
• 负责人: YEKATERINA ZAYTSEVA
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437880
• 关键词: Acetyl Coenzyme A; Acyl Coenzyme A; Adopted; Amino Sugars; Anabolism; Biochemical Pathway; Cancer Etiology; Cell Proliferation; Cessation of life; Characteristics; Clinical Trials; Colon; Colorectal Cancer; Data; Development; Disease; Disease-Free Survival; Drug resistance; Enzymes; Fatty Acids; Fatty-acid synthase; Funding; Gene Expression; Genes; Genetic; Glucose; Glutamine; Glycolysis; Growth; Hexosamines; Human; Immune response; Intestines; Knowledge; Lead; Link; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Membrane; Metabolic; Metabolic Pathway; Metabolism; Mus; Neoplasm Metastasis; Nitrogen; Nuclear Magnetic Resonance; Organoids; Pathway interactions; Pharmacology; Pharmacotherapy; Phase II Clinical Trials; Post-Translational Protein Processing; Process; Production; Prognosis; Protein Glycosylation; Regulation; Research; Resolution; Role; Signal Transduction; Solid; Stable Isotope Labeling; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States; Up-Regulation; Uridine Diphosphate N-Acetylglucosamine; Woman; anti-cancer; cancer cell; cell transformation; colorectal cancer progression; glycosylation; improved; in vivo; inhibitor; link protein; lipid biosynthesis; long chain fatty acid; men; mouse model; neoplastic cell; novel; novel therapeutic intervention; overexpression; oxidation; preclinical study; sugar nucleotide; targeted treatment; therapeutic target; therapeutically effective; transcriptome sequencing; translational impact; tumor; tumor progression; tumorigenesis; uptake

PROJECT SUMMARY Altered metabolism is rapidly emerging as a target for therapeutic intervention in cancer. An increased rate of lipid synthesis in cancer has been recognized as an important aspect of rewired metabolism in transformed cells. Fatty acid synthase (FASN), a key enzyme of lipid synthesis, is actively investigated in pre-clinical studies and clinical trials as a therapeutic target for cancer. Altered glycosylation, also a universal feature of cancer, is associated with cancer progression, reduced immune response, and resistance to drug treatments. The hexosamine biosynthesis pathway (HBP) generates a nucleotide sugar, uridine diphosphate N- acetylglucosamine (UDP-GlcNAc), a key substrate for protein glycosylation. However, the mechanisms of how upregulation of de novo lipid synthesis can contribute to synthesis of UDP-GlcNAc and the effect of FASN- targeted therapy on hexasomine biosynthesis are not yet understood. We developed colorectal cancer (CRC) mouse models with heterozygous and homozygous deletion of FASN in intestine and colon and found that deletion of FASN is associated with a significant decrease in tumor number and an increase in mouse survival. The RNA-seq data and metabolic analysis of tumors show that FASN selectively regulates the levels of enzymes and metabolites within the HBP. Consistantly, we found that expression of FASN alters synthesis of UDP-GlcNAc in human CRC cells and correlates with UDP-GlcNAc level in human CRC tissues. Furthermore, we show that FASN alters O-linked and N-linked protein glycosylation. Therefore, we hypothesize that upregulation of FASN during tumorigenesis enhances synthesis of UDP-GlcNAc via rewiring the metabolic network in CRC cells. In Aim 1, using stable isotope labeling and ultrahigh-resolution mass-spectrometry and nuclear magnetic resonance, we will delineate FASN-mediated metabolic changes in polar metabolites of multiple pathways that supply metabolic subunits to UDP-GlcNAc in vivo. In Aim 2, we will determine the effect of pharmacological inhibition of FASN on synthesis of UDP-GlcNA in human CRC organoids and established the link between expression of FASN and enzymes within the HBP in human CRC tissues. Knowledge of how FASN regulates UDP-GlcNAc synthesis will have a significant translational impact by contributing to better understanding of the mechanisms of metabolic adoptations in cancer cells and identifying new targetable liabilities that would lead to development of more effective therapeutic strategies for CRC. Completion of these studies will also help us advance our ongoing research to better understand how lipid synthesis regulates the landscape of glycosylation in CRC and contribution of these metabolic pathways to CRC progression and metastasis.

项目摘要 改变的代谢正迅速成为癌症治疗干预的靶点。率增加 癌症中的脂质合成已被认为是转化型癌症中重布线代谢的重要方面， 细胞脂肪酸合成酶（Fatty acid synthase，FATS-ET）是脂质合成的关键酶，在临床前研究中十分活跃 作为癌症治疗靶点的研究和临床试验。改变的糖基化，也是 癌症与癌症进展、免疫应答降低和对药物治疗的抗性有关。 己糖胺生物合成途径（HBP）产生核苷酸糖，尿苷二磷酸N- 乙酰葡糖胺（UDP-GlcNAc），蛋白质糖基化的关键底物。然而， 从头脂质合成的上调可有助于UDP-GlcNAc的合成，而FABR 4的作用可促进UDP-GlcNAc的合成。 对己索胺生物合成的靶向治疗尚未了解。我们患上了结肠直肠癌（CRC） 在肠和结肠中具有杂合和纯合缺失的小鼠模型，并发现， 缺失FcB与肿瘤数量的显著减少和小鼠存活率的增加相关。 肿瘤的RNA-seq数据和代谢分析表明，FcB选择性地调节肿瘤细胞的水平。 HBP内的酶和代谢物。一致地，我们发现FGFs的表达改变了 UDP-GlcNAc在人CRC细胞中的表达，并与人CRC组织中的UDP-GlcNAc水平相关。此外，委员会认为， 我们表明，Festival改变O-连接和N-连接蛋白质糖基化。因此，我们假设 在肿瘤发生过程中，FGFAP的上调通过重新连接代谢途径增强UDP-GlcNAc的合成。 CRC信元中的网络。在目标1中，使用稳定同位素标记和超高分辨率质谱， 核磁共振，我们将描绘FASN介导的极性代谢物的代谢变化， 在体内为UDP-GlcNAc提供代谢亚基的多种途径。在目标2中，我们将确定 在人CRC类器官中，研究了芬太尼对UDP-GlcNA合成的药理学抑制作用，并建立了 人CRC组织中HBP内的FRES 1和酶的表达之间的联系。知识如何 FIG. 4调节UDP-GlcNAc合成将通过有助于更好地调节UDP-GlcNAc合成而具有显著的翻译影响。 了解癌细胞代谢适应的机制，并确定新的靶向 这将导致开发更有效的CRC治疗策略。完成这些 研究还将帮助我们推进正在进行的研究，以更好地了解脂质合成如何调节 CRC中糖基化的概况以及这些代谢途径对CRC进展的贡献， 转移