Targeting Tumor Cell Iron Addiction to Achieve Tumor-Selective Cell Death

靶向肿瘤细胞铁成瘾以实现肿瘤选择性细胞死亡

基本信息

批准号：
8788506
负责人：
Scott Dixon
金额：
$ 23.6万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788506
关键词：
Affect Antineoplastic Agents Apoptotic Award Binding Biochemical Biological Assay Biology Cancer cell line Cell Death Cell Proliferation Cell division Cells Cellular biology Cessation of life Chemicals Colorectal Cancer Complex Coupled Cytosol Development Elements Embryo Enzymes Event Fibroblasts Flow Cytometry Genes Genetic Genotype Growth HRAS gene Heme Homeostasis Human Hydroxyl Radical In Vitro Iron KRAS2 gene Knockout Mice Knowledge Life Lipid Peroxidation MEKs Malignant Neoplasms Malignant neoplasm of pancreas Mediating Membrane Mentors Methods Mitochondria Mus Mutation NADP NADPH Oxidase 1 Oncogenic Oxidation-Reduction Pathway interactions Pharmaceutical Preparations Phase Process Production RNA Interference Reactive Oxygen Species Regulation Role Siderophores Site Source Structure Testing Transition Elements Work Xenograft procedure abstracting addiction antitumor drug base cancer cell cell growth cell killing cellular targeting design erastin fibrosarcoma improved in vivo insight iron metabolism killings malignant breast neoplasm mutant neoplastic cell novel novel therapeutic intervention screening small hairpin RNA small molecule tumor tumor growth tumor xenograft uptake

项目摘要

Project Summary/Abstract Tumor cells are 'addicted' to high levels of the transition element iron, which is necessary for the function of iron-dependent enzymes that enable rapid tumor cell division and growth. When improperly sequestered, iron is highly redox active and can catalyze the formation of toxic reactive oxygen species that destroy the cell. It should therefore be possible to kill tumor cells in a selective way by unleashing the redox activity of this element. RAS-RAF-MEK pathway activation is a common event in many cancers that is currently difficult to treat with existing drugs. We previously identified several small molecule compounds that selectively kill a variety of human tumor cells with activating mutations in this pathway. These RAS-selective lethal (RSL) compounds appear to trigger a new form of cell death that exploits the high levels of intracellular iron found in these tumor cells. Here I focus on the lethal mechanism of one RSL, erastin. Using RNA interference (RNAi) screening I identified 11 genes required for erastin-induced death, including the uncharacterized gene ACSF2. I hypothesize that ACSF2 regulates the production of an iron-binding molecule (siderophore) that is necessary for rapid tumor cell proliferation and for the lethal effects of erastin, via regulation of cytosolic iron levels and heme-dependent NADPH oxidase 1 (NOX1) complex activity. I will test this hypothesis in human tumor cells and in Acsf2 knockout mice using genetic, biochemical and chemical assays of cell death, iron metabolism, NOX activity, siderophore production and xenograft tumor growth. This work will define the novel cell death pathway triggered by erastin and similar compounds, provide insight into the role of siderophore-mediated iron uptake in tumor cell growth and significantly improve our ability to target cellular iron addiction to achieve tumor-selective cell death in RAS pathway mutant cancers.

项目摘要/摘要肿瘤细胞被“上瘾”到高水平的过渡元件铁中，这对于功能是必不可少的铁依赖性酶，可以快速肿瘤细胞分裂和生长。当不当隔离时，铁具有高度氧化还原活性，可以催化破坏细胞的有毒活性氧的形成。它因此，应该通过释放其氧化还原活性来以选择性的方式杀死肿瘤细胞元素。 Ras-Raf-Mek途径激活是许多癌症中常见的事件，目前很难用现有药物治疗。我们以前确定了几种选择性杀死A的小分子化合物在该途径中具有激活突变的各种人类肿瘤细胞。这些RAS选择性致命（RSL）化合物似乎触发了一种新形式的细胞死亡形式，它利用了发现的高水平的细胞内铁这些肿瘤细胞。在这里，我专注于一个RSL的致命机制，Erastin。使用RNA干扰（RNAi）筛选I确定了Erastin诱导的死亡所需的11个基因，包括未表征的基因ACSF2。我假设ACSF2调节必要的铁结合分子（铁载体）的产生通过调节胞质铁水平和血红素依赖性NADPH氧化酶1（NOX1）复合活性。我将在人类肿瘤细胞中检验该假设在ACSF2敲除小鼠中，使用遗传，生化和化学测定的细胞死亡，铁代谢， NOX活性，铁载体产生和异种移植肿瘤的生长。这项工作将定义新的细胞死亡由Erastin触发的途径和类似化合物触发的途径，可深入了解铁载体介导的铁的作用吸收肿瘤细胞生长，并显着提高我们靶向细胞成瘾的能力 RAS途径突变体癌症中的肿瘤选择性细胞死亡。