Uridine-cytidine kinase 2 promotes glycolysis and reprograms glioblastoma stem cell characteristics under hypoxic conditions through the PI3K/Akt/HIF-1α pathway

This study aimed to explore key regulatory molecules involved in metabolic alterations clarify the heterogeneity of glioblastoma and develop novel therapeutic strategies. The microarray dataset GSE45117 was retrieved from the Gene Expression Omnibus database to analyze differentially expressed genes (DEGs) glioma stem cell (GSC) populations were enriched via microsphere suspension culture and ALDH+ cell sorting in vitro with the expression of the uridine-cytidine kinase 2 (UCK2) gene compared between stemness and non-stemness populations the UCK2 gene was stably knocked down or overexpressed in GSCs to assess cell invasion migration glucose uptake lactate production and ATP levels. Database analysis revealed high UCK2 expression in cancer stem cells (CSCs) manipulating UCK2 levels affected stemness factors and cell behaviors including proliferation migration invasion and tumor growth UCK2 was more abundant in hypoxic central tumor regions promoting increased glucose uptake and energy production knocking down UCK2 reduced glycolysis and stem cell properties under hypoxia mechanistically UCK2 stabilizes PI3K protein through deubiquitination thereby activating the Akt/HIF-1α pathway. UCK2 plays a pivotal role as a metabolic regulator in glucose metabolism by stabilizing PI3K protein expression via deubiquitination which in turn activates the Akt/HIF-1α signaling pathway.