GPRC5A modulates resistance to temozolomide in glioblastoma through glycolytic reprogramming

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by chemoresistance and poor prognosis. This study investigates the role of GPRC5A in GBM, focusing on its association with chemoresistance to temozolomide (TMZ) and its impact on patient outcomes. Through integrative analyses of the Cancer Therapeutics Response Portal (CTRP) and The Cancer Genome Atlas (TCGA) databases, we identified GPRC5A as significantly upregulated in GBM, correlating with poorer survival and TMZ resistance. Functional assays demonstrated that GPRC5A overexpression enhances tumor sphere formation and stem cell marker expression, such as CD133, suggesting its role in promoting stem-cell-like properties and TMZ resistance. Bioinformatic analyses revealed GPRC5A's involvement in regulating hypoxia and glucose metabolism via the HIF-1 signaling and glycolytic pathways. Mechanistically, GPRC5A interacts with the glycolytic transporter GLUT1, influencing glucose uptake and glycolysis. Silencing GPRC5A increased TMZ sensitivity by reducing GLUT1 stability and glucose uptake, an effect reversible by GLUT1 overexpression. In vivo studies confirmed that GPRC5A silencing reduced tumor growth and improved survival, highlighting its potential as a therapeutic target for overcoming chemoresistance in GBM. These findings underscore the critical role of GPRC5A in GBM and suggest that targeting the GPRC5A-GLUT1 interaction could improve patient outcomes.