Understanding the mechanisms of iron addiction in colon cancer

了解结肠癌铁成瘾的机制

基本信息

批准号：
10442709
负责人：
YATRIK M SHAH
金额：
$ 44.69万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442709
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

项目摘要

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.

抽象的如果及早发现，结直肠癌（CRC）可以得到有效治疗。然而，大多数肿瘤是在治疗选择有限的晚期阶段。评估改变的现象再次兴起癌症生长中的细胞代谢。与正常细胞不同，癌细胞主要依靠有氧糖酵解产生 ATP 生产。有氧糖酵解在 ATP 生成方面效率低下，但糖酵解和 TCA 循环中间体被重新用于生物质的生产。这些研究已经确定了一些有可能成为治疗靶点的关键途径。目前，人们对它知之甚少微量营养素代谢在癌症中的贡献。我们最近的工作已经证实铁的积累是结肠癌生长和进展的关键步骤。结肠癌细胞对高铁上瘾细胞增殖水平。我们已经清楚地表明肿瘤内存在铁的积累与邻近的正常粘膜相比。对铁的遗传或饮食限制会导致铁的急剧下降肿瘤的增殖和进展。然而，目前尚不清楚癌细胞如何维持高铁水平，抵抗铁介导的氧化毒性，并利用铁进行信号传导、生存和生长。我们的目标是确定这些主要差距背后的机制，为结肠铁基治疗奠定基础癌症。我们假设 CRC 绕过了高铁积累的毒性，以促进致癌发信号。细胞铁水平通过肝激素铁调素调节。铁调素与铁结合输出铁转运蛋白导致铁输出的降解和抑制。我们证明结肠肿瘤上皮细胞表达高水平的铁调素和低水平的铁转运蛋白。目标 1 将描述铁调素/铁转运蛋白是否轴是导致铁积累的主要机制，是否可以作为治疗的目标。铁是对于生长至关重要，但对细胞可能具有剧毒。需要严格控制铁含量。熨烫通过芬顿反应导致大量超氧化物形成并引发一种称为非凋亡细胞死亡的形式铁死亡。我们最近的数据表明 CRC 积极抑制铁死亡。目标2就会明白导致抵抗铁诱导损伤的机制。在目标 3 中，我们将解决为什么 CRC 需要高铁含量以维持生长。我们之前的工作表明铁可以直接激活致癌物质激酶通过假定的翻译后修饰（我们称为铁蛋白化）来实现。为了这个目标，我们计划使用细胞模型和患者来源的类器官模型探索铁蛋白化的重要性。实现这些目标将 (i) 揭示铁积累的机制 (ii) 定义新型铁相关的脆弱性，以及 (iii) 描述铁如何驱动 CRC 中的致癌信号传导。这些研究还将重点介绍结直肠癌的新途径、遗传脆弱性和药物靶点。