Understanding the mechanisms of iron addiction in colon cancer

了解结肠癌铁成瘾的机制

• 批准号: 10199967
• 负责人: YATRIK M SHAH
• 金额: $ 45.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10199967
• 关键词: Address; Apical; Area; Binding; Biomass; Bypass; CDC2 gene; Cancer Cell Growth; Cell Death; Cell Proliferation; Cell model; Cells; Cellular Metabolic Process; Citric Acid Cycle; Colon; Colon Carcinoma; Colonic Adenoma; Colonic Neoplasms; Colorectal Cancer; Critical Pathways; Cystine; DNA Damage; Data; Deferoxamine; Development; Diet; Drug Targeting; Embryo; Epithelial; Foundations; Generations; Genetic; Genetic Predisposition to Disease; Glutamates; Goals; Grant; Growth; Hepatic; Hormones; Human; Hydroxyl Radical; Incidence; Inflammatory; Intestines; Iron; Iron Chelation; JAK1 gene; Lead; Leucine Zippers; Lipid Peroxides; Liver; Malignant Neoplasms; Mediating; Metabolism; Micronutrients; Modeling; Mucous Membrane; Mus; Normal Cell; Nutritional Requirements; Oncogenic; Organoids; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Post-Translational Protein Processing; Prevention; Production; Protein Export Pathway; Proteins; Proteome; Radiosensitization; Reaction; Research; Resistance; Role; SLC11A2 gene; STAT3 gene; Signal Transduction; Site; Superoxides; System; Testing; Toxic effect; Work; addiction; aerobic glycolysis; antiporter; base; cancer cell; casein kinase; cell injury; colon cancer progression; colon cancer treatment; colon carcinogenesis; colorectal cancer risk; dietary restriction; epidemiologic data; glutathione peroxidase; hepcidin; iron supplementation; metal transporting protein 1; mouse model; new therapeutic target; novel; novel therapeutics; nuclear factor-erythroid 2; oxidative damage; p21 activated kinase; protein expression; public health relevance; resistance mechanism; targeted treatment; therapeutic target; transcription factor; tumor; uptake

ABSTRACT Colorectal cancer (CRC) can be effectively treated if detected early. However, most tumors are detected at an advanced stage when treatment options are limited. There has been a resurgence in assessing altered cell metabolism in cancer growth. Unlike normal cells, cancer cells rely mainly on aerobic glycolysis for ATP production. Aerobic glycolysis is inefficient in ATP generation, but the glycolytic and TCA cycle intermediates are rerouted for the production of biomass. These studies have led to identification of several critical pathways that have the potential to be therapeutic targets. Currently, much less is known about the contribution of micronutrient metabolism in cancer. Our recent work has established that iron accumulation is critical step in the growth and progression of colon cancer. Colon cancer cells are addicted to high iron levels for cell proliferation. We have clearly shown that there is an accumulation of intra-tumoral iron compared to adjacent normal mucosa. Genetic or dietary restriction of iron leads to a robust decrease in tumor proliferation and progression. However, it is unclear how cancer cells maintain high iron levels, resistant to iron-mediated oxidative toxicity and utilize iron for signaling, survival, and growth. Our goals are to identify mechanism underlying these major gaps to lay the foundation for iron-based therapies in colon cancer. We hypothesize that CRCs bypass the toxicities of high iron accumulation to fuel oncogenic signaling. Cellular iron levels are regulated via a hepatic hormone hepcidin. Hepcidin binds to an iron exporter ferroportin leading to degradation and inhibition of iron export. We show that colon tumor epithelium express high levels of hepcidin and low ferroportin. Aim 1 will delineate if hepcidin/ferroportin axis is the major mechanism leading to iron accumulation and if it can be targeted for therapy. Iron is essential for growth but can be highly toxic to a cell. Iron levels need to be tightly controlled. Iron via the Fenton reaction leads to high superoxide formation and initiates a form of non-apoptotic cell death called ferroptosis. Our recent data suggest that CRCs actively suppress ferroptosis. Aim 2 will understand mechanisms leading to resistance of iron induced damage. In Aim 3 we will address why CRCs need high levels of iron to maintain growth. Our previous work showed that iron can directly activate oncogenic kinases through a putative posttranslational modification we termed ferritinylation. In this Aim we plan to explore the importance of ferritinylation using cell models and patient-derived organoid models. Accomplishing these Aims will (i) uncover mechanisms of iron accumulation (ii) define novel iron related vulnerabilities, and (iii) characterize how iron drives oncogenic signaling in CRC. These studies will also highlight new pathways, genetic vulnerabilities and drug targets for CRC.

抽象的 结直肠癌（CRC）如果早期检测到可以有效治疗。但是，大多数肿瘤在 当治疗方案受到限制时，一个高级阶段。评估变化已有一个复兴 细胞代谢在癌症生长中。与正常细胞不同，癌细胞主要依赖有氧糖酵解的ATP 生产。有氧糖酵解的ATP生成效率低下，但是糖酵解和TCA循环 中间体被重新穿线以生产生物质。这些研究导致了几个 具有治疗靶标的潜力的关键途径。目前，关于 微量营养素代谢在癌症中的贡献。我们最近的工作确定了铁的积累 是结肠癌的生长和发展的关键一步。结肠癌细胞沉迷于高铁 细胞增殖的水平。我们清楚地表明，肿瘤内铁的积累 与相邻的正常粘膜相比。铁的遗传或饮食限制导致强大的下降 肿瘤增殖和进展。但是，尚不清楚癌细胞如何保持高铁水平， 对铁介导的氧化毒性具有抗性，并利用铁来信号传导，生存和生长。我们的目标是 确定这些主要差距的基础机制，以奠定结肠基于铁的疗法的基础 癌症。我们假设CRC绕过了高铁积累的毒性，以燃料致癌 信号。细胞铁水平通过肝激素肝素调节。肝素与铁结合 出口商的铁蛋白会导致铁出口降解和抑制。我们表明结肠肿瘤 上皮表达高水平的肝素和低铁蛋白酶。 AIM 1如果肝素/铁蛋白 轴是导致铁积累的主要机制，以及是否可以将其靶向治疗。铁是 对于生长至关重要，但可能对细胞剧毒。铁水平需要严格控制。铁通过 芬顿反应会导致高氧化物形成，并引发一种称为非凋亡细胞死亡的形式 铁凋亡。我们最近的数据表明，CRC会积极抑制铁铁作用。 AIM 2会理解 导致铁诱导损伤的机制。在AIM 3中，我们将解决为什么CRC需要高 铁的水平以维持生长。我们以前的工作表明铁可以直接激活致癌性 激酶通过推定的翻译后修饰，我们称为铁列蛋白化。在这个目标中，我们计划 使用细胞模型和患者衍生的器官模型探索铁蛋白化的重要性。 实现这些目标将（i）发现铁积累的机制（ii）定义新的铁 相关漏洞，（iii）表征了铁在CRC中驱动致癌信号的方式。这些研究 还将重点介绍CRC的新途径，遗传脆弱性和药物靶标。