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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：
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
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/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

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.

摘要