Hypoxia-induced Metabolic Changes in Cancer

描述（由申请人提供）：我们最近发现了缺氧（人类恶性肿瘤的标志）与癌细胞代谢之间的新联系。我们表明，缺氧在癌细胞中显著诱导了先前未被充分认识的代谢途径，即通过胞质α-酮戊二酸（aKG）还原羧化为异柠檬酸产生胞质乙酰辅酶A（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，是这种现象所必需的，并且转录因子缺氧诱导因子（HIF）和缺氧调节的胞质酶Aco 1可能涉及介导这种缺氧效应。我们的工作强调了缺氧诱导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，我们提出解剖介导缺氧诱导的还原性羧化的分子机制，并验证还原性羧化的关键酶作为体内肿瘤抑制的治疗靶点。

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 a-ketoglutarate (aKG) 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.