PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition.
PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition.
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DOI：
10.1158/2159-8290.cd-16-0612
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发表时间：
2017-04
期刊：
影响因子：
28.2
通讯作者：
Parsons R
中科院分区：
文献类型：
--
作者：
Mathur D;Stratikopoulos E;Ozturk S;Steinbach N;Pegno S;Schoenfeld S;Yong R;Murty VV;Asara JM;Cantley LC;Parsons R
癌症的致癌驱动因素引起的代谢变化有助于肿瘤生长，是癌症治疗的有吸引力的目标。在这里，我们发现 PTEN 突变细胞生长的增加依赖于通过从头嘧啶合成途径的谷氨酰胺通量，这产生了对二氢乳清酸脱氢酶（嘧啶环合成的限速酶）抑制的敏感性。 S期PTEN突变细胞表现出复制叉数量增加，二氢乳清酸脱氢酶抑制剂由于ATR激活不足和复制叉DNA损伤而导致染色体断裂和细胞死亡。我们的研究结果表明，增强的谷氨酰胺通量会导致二氢乳清酸脱氢酶抑制的脆弱性，然后由于 ATR 激活的固有缺陷，导致 PTEN 缺陷细胞的合成致死性。因此，抑制二氢乳清酸脱氢酶可能是 PTEN 突变癌症患者的一种有前景的治疗方法。
Metabolic changes induced by oncogenic drivers of cancer contribute to tumor growth and are attractive targets for cancer treatment. Here, we found that increased growth of PTEN mutant cells was dependent on glutamine flux through the de novo pyrimidine synthesis pathway, which created sensitivity to inhibition of dihydroorotate dehydrogenase, a rate limiting enzyme for pyrimidine ring synthesis. S-phase PTEN mutant cells showed increased numbers of replication forks, and inhibitors of dihydroorotate dehydrogenase led to chromosome breaks and cell death due to inadequate ATR activation and DNA damage at replication forks. Our findings indicate that enhanced glutamine flux generates vulnerability to dihydroorotate dehydrogenase inhibition, which then causes synthetic lethality in PTEN deficient cells due to inherent defects in ATR activation. Inhibition of dihydroorotate dehydrogenase could thus be a promising therapy for patients with PTEN mutant cancers.