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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要代谢改变正在迅速成为癌症治疗干预的目标。增加的比率癌症中的脂质合成已被认为是转化后代谢重组的一个重要方面细胞。脂肪酸合酶（FASN）是脂质合成的关键酶，在临床前研究中得到积极研究作为癌症治疗靶点的研究和临床试验。糖基化改变，也是糖基化的普遍特征癌症，与癌症进展、免疫反应降低和对药物治疗的耐药性有关。己糖胺生物合成途径 (HBP) 产生核苷酸糖、尿苷二磷酸 N- 乙酰氨基葡萄糖 (UDP-GlcNAc)，蛋白质糖基化的关键底物。然而，其机制如何脂质从头合成的上调有助于 UDP-GlcNAc 的合成以及 FASN- 的作用六体胺生物合成的靶向治疗尚不清楚。我们患上了结直肠癌（CRC）肠道和结肠中 FASN 杂合和纯合缺失的小鼠模型发现 FASN 的缺失与肿瘤数量的显着减少和小鼠存活率的增加有关。 RNA-seq数据和肿瘤代谢分析表明FASN选择性调节 HBP 内的酶和代谢物。我们一致发现 FASN 的表达改变了人 CRC 细胞中的 UDP-GlcNAc 与人 CRC 组织中的 UDP-GlcNAc 水平相关。此外，我们发现 FASN 改变 O-连接和 N-连接蛋白质糖基化。因此，我们假设肿瘤发生过程中 FASN 的上调通过重新连接代谢增强 UDP-GlcNAc 的合成 CRC 单元中的网络。在目标 1 中，使用稳定同位素标记和超高分辨率质谱分析核磁共振，我们将描绘 FASN 介导的极性代谢物的代谢变化体内向 UDP-GlcNAc 提供代谢亚基的多种途径。在目标 2 中，我们将确定效果 FASN 对人 CRC 类器官中 UDP-GlcNA 合成的药理学抑制作用，并建立人类结直肠癌组织中 FASN 表达与 HBP 内酶之间的联系。知道如何做 FASN 监管 UDP-GlcNAc 合成将产生重大转化影响，有助于更好地了解癌细胞代谢采用的机制并确定新的靶向责任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 中糖基化的情况以及这些代谢途径对 CRC 进展的贡献转移。