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FDH: A Novel Determinant of Tumor Suppression

FDH：肿瘤抑制的新决定因素

基本信息

批准号：
8895055
负责人：
SERGEY A KRUPENKO
金额：
$ 24.09万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2014-09-12 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895055
关键词：
Actins Address Anabolism Apoptosis Apoptotic Binding Biochemical Reaction Cancer Biology Cancer cell line Carbon Cell Death Cell Survival Cell physiology Cells Complex Cytoplasm DHFR gene DNA DNA Repair Diagnostic Diet Disease Down-Regulation Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Epidemiologic Studies Equilibrium Evaluation Folate Folic Acid Deficiency Formyltetrahydrofolates Genes Goals Growth Human Hypermethylation Impairment Investigation Kidney Knock-out Link Liver MAPK8 gene MAPK9 gene Malignant - descriptor Malignant Neoplasms Metabolic Metabolic Pathway Metabolism Methylation Molecular NADP Names Normal Cell Nucleotide Biosynthesis Onset of illness Oxidoreductase Pathway interactions Phosphorylation Physiological Preventive Process Protein p53 Proteins Publishing Purines RNA biosynthesis Reaction Regulation Resistance Role Signal Transduction Stream Stress Supplementation Susceptibility Gene Targeted Research Testing Tetrahydrofolates Transcriptional Activation Tumor Suppression Tumor Suppressor Proteins Tumor Tissue base cancer cell carcinogenesis cell motility cytotoxicity design folic acid metabolism in vivo insight mouse model mutant neoplastic cell novel promoter purine research study tumor tumor initiation tumorigenesis tumorigenic

项目摘要

ABSTRACT The overall goal of this proposal is to characterize the novel tumor suppressor activity of a key metabolic enzyme and determine the mechanisms transforming metabolic effects into regulation of proliferation. FDH (10-formyltetrahydrofolate dehydrogenase) irreversibly converts 10-formyltetrahydrofolate, an essential substrate for de novo purine biosynthesis, to tetrahydrofolate. Through depletion of this substrate, FDH can restrict purine biosynthesis. In turn, this interferes with important downstream cellular processes, including DNA/RNA biosynthesis and DNA repair. Because of this critical metabolic function, down-regulation of FDH in cancer cells was predicted to be pro-survival. Indeed, we have initially made the important observation that FDH is strongly and ubiquitously down-regulated in tumors through the promoter hypermethylation. We have further demonstrated that moderate FDH expression in FDH-deficient cancer cells induces apoptotic cell death. In contrast, non-cancer cells are insensitive to high levels of the enzyme. Therefore, it is proposed that cancer cells silence the FDH gene in order to escape cytotoxicity. Studies of phenotypic effects upon reactivation of normal FDH expression in FDH-deficient tumor cells have further explored JNK1/2 and p53 as key components of FDH-induced apoptotic signaling, and determined DHFR and folate supplementation as proliferation rescue factors. Importantly, a novel pathway linking FDH, through intracellular folate regulation, to control of cell motility, was discovered. The current proposal extends previous studies of antiproliferative mechanisms of FDH, and related folates, to direct interaction with p53 and evaluation of its role in vivo in mouse model. Our central hypothesis is that FDH down-regulation through promoter hypermethylation is one of the important means by which malignancies gain pro-survival advantage over normal cells. We further suggest that FDH exerts its regulatory effects through multiple mechanisms. The Specific Aims to probe these mechanisms and test our hypothesis are: (1) Investigate the functional interaction of FDH with p53 tumor suppressor protein in cytoplasm. (2) Determine the impact of FDH silencing on tumor initiation/progression using FDH deficient mouse model. Investigation of the critical role of FDH, in cancer cell survival/induction of folate stress at the onset of the disease, will provide important insight into the malignant process itself and link deregulation of key metabolic pathways to cancer disease, as well as establish new targets for diagnostics of the malignant transformation.

摘要该提案的总体目标是表征一种关键代谢产物的新型肿瘤抑制活性，酶和确定机制转化为调节增殖代谢的影响。FDH （10-甲酰四氢叶酸脱氢酶）不可逆地转化10-甲酰四氢叶酸，一种必需的嘌呤从头生物合成的底物转化为四氢叶酸。通过消耗这种底物，FDH可以限制嘌呤生物合成。反过来，这会干扰重要的下游细胞过程，包括 DNA/RNA生物合成和DNA修复。由于这一关键的代谢功能，FDH的下调，癌细胞被预测是促存活的。事实上，我们初步提出了重要的意见， FDH通过启动子超甲基化在肿瘤中强烈且普遍地下调。我们有进一步证明了在FDH缺陷型癌细胞中适度的FDH表达诱导凋亡细胞，死亡相比之下，非癌细胞对高水平的酶不敏感。因此提议癌细胞沉默FDH基因以逃避细胞毒性。表型效应的研究 FDH缺陷肿瘤细胞中正常FDH表达的再激活进一步研究了JNK 1/2和p53作为关键成分的FDH诱导的细胞凋亡信号，并确定DHFR和叶酸补充剂，增殖拯救因子重要的是，一种新的途径连接FDH，通过细胞内叶酸调节，控制细胞的运动。目前的建议扩展了以前的抗增殖研究， FDH和相关叶酸直接与p53相互作用的机制及其在体内小鼠模型我们的中心假设是，通过启动子高甲基化的FDH下调是这是恶性肿瘤获得优于正常细胞的促存活优势的重要手段。我们进一步建议外佣是透过多种机制发挥其调节作用。具体目的是探讨这些研究FDH与p53肿瘤的相互作用机制，验证我们的假设：（1）研究FDH与p53肿瘤的相互作用胞质抑制蛋白。(2)使用以下方法确定FDH沉默对肿瘤起始/进展的影响： FDH缺陷型小鼠模型。研究FDH在癌细胞存活/叶酸诱导中的关键作用在疾病开始时的压力，将提供重要的洞察恶性过程本身和联系解除对癌症疾病关键代谢途径的管制，以及建立诊断癌症的新目标。恶性转化。