Abstract
Gastric cancer cell progression is intricately linked to their metabolic status. Neddylation inhibition, such as MLN4924, demonstrates anti-tumor effects by impacting crucial cellular processes. However, the effects of Neddylation modification on gastric cancer cell metabolism and underlying mechanisms remain poorly understood. Our study firstly confirmed the anti-tumor effect of neddylation inhibition by MLN4924. Based on metabolite analysis, MLN4924 promoted glucose metabolism and nucleotide synthesis. Mechanistically, MLN4924 increased the accumulation of HIF-1α by inhibiting cullin 2 neddylation, which led to the upregulation of glucose transporter 1 (GLUT1) expression and activity. Importantly, the combination Interestingly, attenuation of MLN4924-induced apoptosis occurred upon either knocking down or inhibiting GLUT1, emphasizing its role in mitigating MLN4924's apoptotic activity. We observed metabolic alterations, notably an upregulation of GLUT1, a key protein associated with metabolic regulation. This led to increased glucose uptake and metabolism within gastric cancer cells, ultimately diminishing MLN4924’s anti-tumor effectiveness. Furthermore, our findings revealed that HIF-1α mediated the upregulation of GLUT1 induced by MLN4924. In mouse models bearing MGC-803 cell xenografts, co-administration of a GLUT1-specific inhibitor remarkably enhanced the therapeutic efficacy of MLN4924. Combining MLN4924 with a GLUT1 inhibitor presents a potential novel therapeutic strategy for gastric cancer treatment.