Synthetic lethality of glutaminolysis inhibition, autophagy inactivation and asparagine depletion in colon cancer.
Synthetic lethality of glutaminolysis inhibition, autophagy inactivation and asparagine depletion in colon cancer.
复制标题
结肠癌中谷氨酰胺分解抑制、自噬失活和天冬酰胺消耗的综合致死率
DOI：
10.18632/oncotarget.16844
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发表时间：
2017-06-27
期刊：
影响因子：
--
通讯作者：
Jin H
中科院分区：
文献类型：
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作者：
Li J;Song P;Zhu L;Aziz N;Zhou Q;Zhang Y;Xu W;Feng L;Chen D;Wang X;Jin H
癌细胞对新陈代谢进行重新编程，以协调其快速生长。他们依赖谷氨酰胺代谢来合成三磷酸腺苷和大分子生物合成。在这项研究中，我们报告了谷氨酰胺的剥夺阻碍了细胞的生长并诱导了自噬。氯喹对自噬的抑制作用明显增强谷氨酰胺饥饿诱导的细胞生长抑制和细胞凋亡激活。用L-天冬酰胺酶剥夺天冬酰胺加剧了谷氨酰胺饥饿和自噬抑制引起的生长抑制。与谷氨酰胺饥饿类似，目前正在进行临床评估的一种化学抑制剂抑制谷氨酰胺代谢，与氯喹和L天冬酰胺酶一样，是合成致命的，这两种药物分别被批准用于治疗疟疾和白血病。综上所述，抑制谷氨酰胺分解与自噬抑制和天冬酰胺耗尽是综合致死的。因此，靶向谷氨酰胺降解可能是结直肠癌治疗的一种有前途的方法。
Cancer cells reprogram metabolism to coordinate their rapid growth. They addict on glutamine metabolism for adenosine triphosphate generation and macromolecule biosynthesis. In this study, we report that glutamine deprivation retarded cell growth and induced prosurvival autophagy. Autophagy inhibition by chloroquine significantly enhanced glutamine starvation induced growth inhibition and apoptosis activation. Asparagine deprivation by L-asparaginase exacerbated growth inhibition induced by glutamine starvation and autophagy blockage. Similar to glutamine starvation, inhibition of glutamine metabolism with a chemical inhibitor currently under clinical evaluation was synthetically lethal with chloroquine and L-asparaginase, drugs approved for the treatment of malaria and leukemia, respectively. In conclusion, inhibiting glutaminolysis was synthetically lethal with autophagy inhibition and asparagine depletion. Therefore, targeting glutaminolysis could be a promising approach for colorectal cancer treatment.