Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2
Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2
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DOI：
10.1038/s41388-018-0589-1
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发表时间：
2019-04-04
期刊：
影响因子：
8
通讯作者：
Gotoh, Noriko
中科院分区：
文献类型：
--
作者：
Nishimura, Tatsunori;Nakata, Asuka;Gotoh, Noriko
肿瘤复发可归因于癌症干细胞样细胞（CSC），其代谢机制目前仍不清楚。在这里，我们发现了叶酸介导的一碳（1C）代谢的关键作用，涉及线粒体亚甲基四氢叶酸脱氢酶2（MTHFD 2）及其下游嘌呤合成途径。MTHFD 2敲低大大降低了肿瘤发生和干细胞样特性，这与嘌呤核苷酸缺乏有关，并导致嘌呤合成途径的最终中间体5-氨基咪唑甲酰胺核糖核苷酸（AICAR）的显著积累。对靶向药物吉非替尼具有获得性耐药性的肺癌细胞（由β-连环蛋白途径的组分的表达升高引起）表现出增加的干细胞样特性和增强的MTHFD 2表达。MTHFD 2敲除或AICAR治疗降低了这些吉非替尼耐药癌细胞的干细胞样特性并恢复了吉非替尼敏感性。此外，MTHFD 2在吉非替尼敏感的肺癌细胞中的过表达赋予了对吉非替尼的抗性。因此，MTHFD 2介导的线粒体1C代谢对于癌症干细胞样性质和通过消耗AICAR对包括吉非替尼在内的药物的抗性似乎是关键的，导致AICAR的细胞内库的耗尽。由于CSC依赖于MTHFD 2，因此靶向MTHFD 2的治疗可以根除肿瘤并预防复发。
Tumor recurrence is attributable to cancer stem-like cells (CSCs), the metabolic mechanisms of which currently remain obscure. Here, we uncovered the critical role of folate-mediated one-carbon (1C) metabolism involving mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and its downstream purine synthesis pathway. MTHFD2 knockdown greatly reduced tumorigenesis and stem-like properties, which were associated with purine nucleotide deficiency, and caused marked accumulation of 5-aminoimidazole carboxamide ribonucleotide (AICAR)-the final intermediate of the purine synthesis pathway. Lung cancer cells with acquired resistance to the targeted drug gefitinib, caused by elevated expression of components of the beta-catenin pathway, exhibited increased stem-like properties and enhanced expression of MTHFD2. MTHFD2 knockdown or treatment with AICAR reduced the stem-like properties and restored gefitinib sensitivity in these gefitinib-resistant cancer cells. Moreover, overexpression of MTHFD2 in gefitinib-sensitive lung cancer cells conferred resistance to gefitinib. Thus, MTHFD2-mediated mitochondrial 1C metabolism appears critical for cancer stem-like properties and resistance to drugs including gefitinib through consumption of AICAR, leading to depletion of the intracellular pool of AICAR. Because CSCs are dependent on MTHFD2, therapies targeting MTHFD2 may eradicate tumors and prevent recurrence.