Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells
Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells
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DOI：
10.1016/j.cmet.2018.10.014
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发表时间：
2019-02-05
期刊：
影响因子：
29
通讯作者：
Neuzil, Jiri
中科院分区：
文献类型：
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作者：
Bajzikova, Martina;Kovarova, Jaromira;Neuzil, Jiri
没有线粒体DNA(MtDNA)的癌细胞不会形成肿瘤，除非它们通过从宿主基质获得的线粒体重建氧化磷酸化(OXPHOS)。为了了解为什么功能性呼吸对肿瘤的发生至关重要，我们使用了线粒体DNA耗尽细胞和OXPHOS的遗传操作的时间分辨分析肿瘤形成。我们发现，依赖呼吸相关的二氢罗酸脱氢酶(DHODH)的嘧啶生物合成是克服细胞周期停滞所必需的，而线粒体ATP的产生对于肿瘤的发生是必不可少的。线粒体转移后，随着复合体III/IV活性的恢复和辅酶Q的氧化还原循环，或通过引入替代氧化酶，mtDNA缺陷细胞中的潜伏DHODH被完全激活。此外，DHODH的缺失干扰了具有全功能OXPHOS的细胞的肿瘤形成，而线粒体ATP合成酶的破坏几乎没有影响。我们的结果表明，DHODH驱动的嘧啶生物合成是将呼吸作用与肿瘤发生联系起来的重要途径，表明DHODH抑制剂是潜在的抗癌药物。
Cancer cells without mitochondrial DNA ( mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA-depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with restoration of complex III/IV activity and coenzyme Q redox-cycling after mitochondrial transfer, or by introduction of an alternative oxidase. Further, deletion of DHODH interferes with tumor formation in cells with fully functional OXPHOS, while disruption of mitochondrial ATP synthase has little effect. Our results show that DHODH-driven pyrimidine biosynthesis is an essential pathway linking respiration to tumorigenesis, pointing to inhibitors of DHODH as potential anti-cancer agents.