Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer.

在致癌信号的驱动下，癌细胞所表现出的谷氨酰胺成瘾通常导致实体瘤中谷氨酰胺的严重消耗。尽管肿瘤细胞经常经历这种营养环境，但是谷氨酰胺缺乏对细胞对DNA损伤和化学疗法的反应的影响仍不清楚。在这里，我们表明，谷氨酰胺缺乏症，通过减少α-酮戊二酸，抑制AlkB同源（ALKBH）酶的活性，并诱导DNA烷基化损伤。结果，谷氨酰胺剥夺或谷氨酰胺酶抑制剂治疗可触发DNA损伤积累，而与细胞死亡无关。另外，在ALKBH缺陷的细胞中消除了低谷氨酰胺诱导的DNA损伤。重要的是，我们证明了谷氨酰胺酶抑制剂6-Diazo-5-oxo-L-正亮氨酸（DON）或CB-839，在体外和体内都使癌细胞对烷基化剂过敏。总之，本研究中确定的谷氨酰胺代谢和DNA修复途径之间的相互影响突出了代谢应激在癌症的基因组不稳定性和治疗反应中的潜在作用。