Hypoxia-induced Metabolic Changes in Cancer

缺氧引起的癌症代谢变化

基本信息

批准号：
8657912
负责人：
Othon Iliopoulos
金额：
$ 30.98万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-20 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657912
关键词：
Acute leukemia Area Cancer Biology Cell Line Cells Citric Acid Cycle Data Environment Enzymes Fatty Acids Gene Targeting Generations Genes Glioblastoma Glioma Glucose Glutamine Goals Growth Human Hypoxia Hypoxia Inducible Factor In Vitro Individual Isocitrate Dehydrogenase Isocitrates Learning Link Malignant Neoplasms Mediating Metabolic Metabolic Pathway Metabolic stress Metabolism Mitochondria Molecular Mutate Mutation Nature Normal Cell Oncogenic Oxidative Phosphorylation Pathway interactions Phosphotransferases Production Proteins Renal Cell Carcinoma Renal carcinoma Role Series Signal Transduction Solid Neoplasm Technology Testing Time Tumor Suppression Work alpha ketoglutarate cancer cell cancer therapy carboxylation cell growth in vitro testing in vivo insight isocitrate killings lipid biosynthesis metaplastic cell transformation mutant novel paralogous gene polypeptide research study small hairpin RNA small molecule therapeutic target therapy development transcription factor tumor tumor metabolism

项目摘要

DESCRIPTION (provided by applicant): We recently identified a novel link between hypoxia, which is a hallmark of human malignancies, and cancer cell metabolism. We showed that hypoxia dramatically induces a previously under-appreciated metabolic pathway in cancer cells, namely the generation of cytosolic Acetyl-Coa (AcCoA) by reductive carboxylation of cytosolic ?-ketoglutarate (?KG) to isocitrate. Our preliminary data indicate that Isocitrate Dehydrogenase 1, an enzyme mutated in gliomas and acute leukemias, is necessary for this phenomenon and that the transcription factors Hypoxia Inducible Factors (HIFs) and the hypoxia-regulated cytosolic enzyme Aco1 are likely implicated in mediating this hypoxia effect. Our work highlights that hypoxia-induced metabolic changes of cancer cells present an opportunity for development of therapies targeting a broad range of human malignancies. In this application we propose to dissect the molecular mechanism(s) mediating the hypoxia-induced reductive carboxylation by and to validate critical enzymes of reductive carboxylation as therapeutic targets for tumor suppression in vivo.

描述（由申请人提供）：我们最近发现缺氧（人类恶性肿瘤的标志）与癌细胞代谢之间存在新的联系。我们发现，缺氧会显着诱导癌细胞中一条以前未被充分认识的代谢途径，即通过胞质 β-酮戊二酸 (?KG) 还原羧化为异柠檬酸来生成胞质乙酰辅酶 (AcCoA)。我们的初步数据表明，异柠檬酸脱氢酶 1（一种在神经胶质瘤和急性白血病中突变的酶）对于这种现象是必要的，并且转录因子缺氧诱导因子 (HIF) 和缺氧调节的胞质酶 Aco1 可能与介导这种缺氧效应有关。。我们的工作强调，缺氧引起的癌细胞代谢变化为开发针对广泛人类恶性肿瘤的疗法提供了机会。在本申请中，我们建议剖析介导缺氧诱导的还原羧化的分子机制，并验证还原羧化的关键酶作为体内肿瘤抑制的治疗靶点。