Profiling iron-regulated metabolic reprogramming for nucleotide biosynthesis in colon tumors

分析结肠肿瘤中核苷酸生物合成的铁调节代谢重编程

基本信息

批准号：
10202652
负责人：
Xiang Xue
金额：
$ 26.37万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10202652
关键词：
Affect Animal Model Aspartate Automobile Driving Biology Cancer Etiology Cancer Model Carbamyl Phosphate Cell Proliferation Cell Survival Cells Cessation of life Clinic Colon Colonic Neoplasms Colorectal Cancer Consumption DNA Polymerase III DNA biosynthesis DNA-Directed DNA Polymerase Data Deferoxamine Development Diet Dihydroorotase Enzymes Exhibits Future Genetic Glucose Glutamine Glycolysis Goals Growth Human Hypoxia Incidence Iron Iron Chelation Knock-out Knowledge Ligase Link MCC gene Macronutrients Nutrition Malignant Neoplasms Measures Mediating Medicine Metabolic Metabolism Metals Methods Molecular Mus New Mexico Normal Cell Nucleotide Biosynthesis Nucleotides PDH kinase Pathway interactions Patients Pentosephosphate Pathway Pharmacology Polymerase Pyrimidine Repression Role SLC2A1 gene Signal Transduction TP53 gene Testing Therapeutic Tissues Tumor-Derived Universities Uridine Kinase Work base cBioPortal cancer cell cancer genomics cancer risk cell growth colon cancer patients colon carcinogenesis colon tumorigenesis colorectal cancer progression epidemiology study glucose metabolism improved inhibitor/antagonist iron supplement metabolomics neoplastic cell novel therapeutic intervention novel therapeutics nucleotide metabolism stable isotope transcarbamylase tumor tumor growth

项目摘要

Colorectal cancer (CRC) is the third leading cause of cancer-related death in US. Understanding the mechanisms of CRC development is essential to improve treatment. Increased tissue iron in both mice and humans is associated with increased colon tumorigenesis. However, the precise mechanisms for how iron contributes to colon carcinogenesis are still unclear. The metabolic differences between normal and cancer cells are being interrogated to uncover potential new therapeutic approaches. Many tumor cells exhibit increased glucose consumption, glutamine metabolism and nucleotide synthesis. This proposal will test the central hypothesis that iron-driven cellular metabolic reprograming promotes DNA synthesis and colon tumorigenesis. This hypothesis is based on: 1) iron supplement increases, whereas chelation of iron by deferoxamine (DFO) inhibits the growth and cell proliferation of patient-derived CRC colonoids; 2) treating mice with high-iron diet increases, while low-iron diet decreases colon tumor multiplicity, incidence and progression; 3) metabolomics analysis reveals that excess iron impacts glucose-stimulated nucleotide synthesis by promoting hypoxia-independent “Warburg-like effect” and fueling pentose phosphate pathway in colonoids; 4) iron restriction by DFO leads to glutamine accumulation and reduction of metabolites in nucleotide biosynthesis pathways in colonoids. Based on these observations, the proposal will test the following three Specific Aims: 1) Define the mechanism by which excess iron affects glucose-stimulated DNA biosynthesis in CRC; 2) Study the impact of iron restriction on glutamine-dependent nucleotide synthesis in CRC; 3) Characterize the role of a DNA polymerase in iron-regulated nucleotide metabolism and CRC. We will utilize highly clinic-relevant CRC patient-derived colonoid culture, metabolomics analysis, and various animal models. Accomplishing the above Aims will provide precise molecular mechanisms for how tumor cells are adapted to iron signal to synthesize nucleotides for facilitating tumor proliferation. These studies will fill our knowledge gap of how iron regulates CRC growth and progression.

结直肠癌（CRC）是美国与癌症相关死亡的欺骗原因 CRC发育的机制对于提高了小鼠的组织至关重要。人类与结肠肿瘤的增加有关。造成结肠癌的作用仍不清楚。细胞正在审问以发现潜在的新治疗方法。增加葡萄糖消耗，谷氨酰胺代谢和核苷酸合成。铁驱动的细胞代谢重编程促进了DNA合成和结肠的中心假设肿瘤发生。该假设基于：1）铁的增加脱氧胺（DFO）抑制了治疗小鼠的患者CRC结构化的生长和细胞增殖随着高铁饮食的增加，低铁饮食将结肠肿瘤的多重性，发病率和进度降低； 3）代谢组学分析启示过多铁会影响葡萄糖刺激的核苷酸合成促进缺氧 - 类似于沃尔伯格的效应，并在菌群中加油。 DFO限制铁导致谷氨酰胺的积累和核苷酸生物合成中代谢产物的减少 Coloronoid中的途径。定义过量铁影响CRC中葡萄糖诱导的DNA生物合成的机制；铁限制对CRC中谷氨酸依赖性核苷酸合成的影响；铁制的核苷酸代谢和CRC中的DNA聚合酶。患者衍生的结肠培养，代谢组学分析和各种动物模型目的将使肿瘤细胞如何适应铁信号的分子机制来合成核苷酸促进肿瘤增殖。 CRC的增长和进步。