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

• 批准号: 10629363
• 负责人: Xiang Xue
• 金额: $ 26.11万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 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/10629363
• 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 Chelating Agents; 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; PDH kinase; Pathway interactions; Patients; Pentosephosphate Pathway; Polymerase; Proliferating; Pyrimidine; Repression; Role; SLC2A1 gene; Signal Transduction; TP53 gene; Testing; Tissues; Universities; Uridine Kinase; Work; 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; iron supplement; metabolomics; neoplastic cell; novel therapeutic intervention; novel therapeutics; nucleotide metabolism; pharmacologic; stable isotope; therapeutic target; transcarbamylase; tumor; tumor growth

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）是美国癌症相关死亡的第三大原因。了解 CRC发展机制对于改善治疗至关重要。小鼠和小鼠的组织铁含量均增加 人类与结肠肿瘤发生增加有关。然而，铁的精确机制 导致结肠癌发生的因素仍不清楚。正常人和癌症之间的代谢差异 正在研究细胞以发现潜在的新治疗方法。许多肿瘤细胞表现出 葡萄糖消耗、谷氨酰胺代谢和核苷酸合成增加。该提案将测试 中心假设是铁驱动的细胞代谢重编程促进 DNA 合成和结肠 肿瘤发生。该假设基于：1）铁的补充量增加，而铁的螯合通过 去铁胺 (DFO) 抑制患者来源的 CRC 结肠样细胞的生长和细胞增殖； 2）治疗小鼠 随着高铁饮食的增加，而低铁饮食则降低结肠肿瘤的多样性、发生率和进展； 3）代谢组学分析表明，过量的铁通过以下方式影响葡萄糖刺激的核苷酸合成： 促进不依赖于缺氧的“Warburg 样效应”并促进类结肠中的戊糖磷酸途径； 4） DFO 限制铁会导致谷氨酰胺积累并减少核苷酸生物合成中的代谢物 结肠中的通路。根据这些观察，该提案将测试以下三个具体目标：1) 确定过量铁影响 CRC 中葡萄糖刺激的 DNA 生物合成的机制； 2）研究 铁限制对结直肠癌中谷氨酰胺依赖性核苷酸合成的影响； 3）描述角色的特征 铁调节核苷酸代谢和 CRC 中的 DNA 聚合酶。我们将利用与临床高度相关的 CRC 患者来源的结肠培养、代谢组学分析和各种动物模型。完成以上任务 目标将为肿瘤细胞如何适应铁信号来合成提供精确的分子机制 促进肿瘤增殖的核苷酸。这些研究将填补我们关于铁如何调节的知识空白 CRC 的生长和进展。