Wu Han, Zhang Jialin, Wang Qiujie, Li Zijiao, Li Linlin, Xie Ya
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Sci Rep. 2025 Feb 19;15(1):6072. doi: 10.1038/s41598-025-90963-8.
KRAS mutations can cause metabolic reprogramming in ovarian cancer, leading to an increased metastatic capacity. This study investigated the metabolic reprogramming changes induced by KRAS mutations in ovarian cancer and the mechanism of action of metformin combined with a glutaminase 1 inhibitor (CB-839). KRAS-mutant ovarian cancer accounted for 14% of ovarian cancers. The expression of glucose metabolism-related (PFKFB3, HK2, GLUT1, and PDK2) and glutamine metabolism-related enzymes (GLS1 and ASCT2) was elevated in KRAS-mutant ovarian cancer cells compared with that in wild-type cells. KRAS-mutant cells had a higher aerobic oxidative capacity than did wild-type cells. Metformin inhibited proliferation, the expression of glucose metabolism-related enzymes, and the aerobic oxidative capacity of KRAS-mutant cells compared with those of control cells. Furthermore, it enhanced the expression of glutamine metabolism-related enzymes in KRAS-mutant cells. Metformin combined with CB-839 inhibited the proliferation and aerobic oxidation of KRAS-mutant cells to a greater extent than that observed in wild-type cells. Additionally, the inhibitory effects of metformin and CB-839 in the KRAS-mutant ovarian cancer NOD-SCID mouse model were significantly stronger than those in the drug-alone group. KRAS mutations lead to enhanced glucose and glutamine metabolism in ovarian cancer cells, which was inhibited by metformin combined with CB-839.
KRAS突变可导致卵巢癌发生代谢重编程，进而增加转移能力。本研究调查了KRAS突变在卵巢癌中诱导的代谢重编程变化以及二甲双胍联合谷氨酰胺酶1抑制剂（CB-839）的作用机制。KRAS突变型卵巢癌占卵巢癌的14%。与野生型细胞相比，KRAS突变型卵巢癌细胞中葡萄糖代谢相关酶（PFKFB3、HK2、GLUT1和PDK2）和谷氨酰胺代谢相关酶（GLS1和ASCT2）的表达升高。KRAS突变型细胞比野生型细胞具有更高的有氧氧化能力。与对照细胞相比，二甲双胍抑制了KRAS突变型细胞的增殖、葡萄糖代谢相关酶的表达以及有氧氧化能力。此外，它增强了KRAS突变型细胞中谷氨酰胺代谢相关酶的表达。二甲双胍联合CB-839比野生型细胞更能抑制KRAS突变型细胞的增殖和有氧氧化。此外，在KRAS突变型卵巢癌NOD-SCID小鼠模型中，二甲双胍和CB-839的抑制作用明显强于单药组。KRAS突变导致卵巢癌细胞中葡萄糖和谷氨酰胺代谢增强，而二甲双胍联合CB-839可抑制这种增强。
