Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase
Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase
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DOI：
10.1038/nature10363
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发表时间：
2011-09-08
期刊：
影响因子：
64.8
通讯作者：
Gottlieb, Eyal
中科院分区：
文献类型：
--
作者：
Frezza, Christian;Zheng, Liang;Gottlieb, Eyal
延胡索酸水合酶（FH）是三羧酸循环（TCA循环）中的一种酶，它催化延胡索酸水合生成苹果酸。FH的种系突变与遗传性平滑肌瘤病和肾细胞癌（HLRCC）有关（1）。先前已证明，FH缺失会导致延胡索酸积累，从而在正常氧张力下激活缺氧诱导因子（HIFs）（2 - 4）。然而，到目前为止，尚未有机制能够解释细胞在TCA循环功能缺失的情况下如何存活。在此，我们使用新鉴定的基因修饰的小鼠肾细胞（其中Fh1已被删除），并应用新开发的这些细胞的代谢计算机模型来预测并通过实验验证一条线性代谢途径，该途径从谷氨酰胺摄取开始，到Fh1缺陷细胞的胆红素排泄结束。这条涉及血红素生物合成和降解的途径使Fh1缺陷细胞能够利用积累的TCA循环代谢物，并允许部分线粒体NADH产生。我们预测并证实，针对这条途径将使Fh1缺陷细胞无法存活，而对含野生型Fh1的细胞无影响。这项工作不仅仅是确定了在Fh1缺陷细胞中诱导的代谢途径，还证明了血红素氧合抑制与Fh1缺陷相结合具有合成致死性，为治疗HLRCC患者提供了一个新的潜在靶点。
Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC)(1). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions(2-4). However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells nonviable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.