Integrin αvβ3 Engagement Regulates Glucose Metabolism and Migration through Focal Adhesion Kinase (FAK) and Protein Arginine Methyltransferase 5 (PRMT5) in Glioblastoma Cells

SIMPLE SUMMARY: Interactions of integrins with the extracellular matrix play a key role in cancer cell migration, invasion, and growth. However, whether integrin engagement promotes cancer progression through metabolic reprogramming has not been completely understood. This study investigates the role and mechanism of integrin αvβ3 engagement with its ligand in metabolic reprogramming. The data support that integrin αvβ3 plays an important role in increased glucose uptake and aerobic glycolysis, as well as in decreased mitochondrial oxidative phosphorylation, in glioblastoma cells. In addition, the data imply that focal adhesion kinase (FAK) and protein arginine methyltransferase 5 (PRMT5) are likely downstream effectors of integrin αvβ3, and regulate metabolic shift toward glycolysis. These findings provide new insight into how cancer cells regulate their metabolism based on microenvironmental cues transmitted by integrin and extracellular matrix proteins, and how the signals eventually translate to metabolic modifications coupled with changes in cell behavior, including migration, invasion, and growth. ABSTRACT: Metabolic reprogramming promotes glioblastoma cell migration and invasion. Integrin αvβ3 is one of the major integrin family members in glioblastoma multiforme cell surface mediating interactions with extracellular matrix proteins that are important for glioblastoma progression. The role of αvβ3 integrin in regulating metabolic reprogramming and its mechanism of action have not been determined in glioblastoma cells. Integrin αvβ3 engagement with osteopontin promotes glucose uptake and aerobic glycolysis, while inhibiting mitochondrial oxidative phosphorylation. Blocking or downregulation of integrin αvβ3 inhibits glucose uptake and aerobic glycolysis and promotes mitochondrial oxidative phosphorylation, resulting in decreased migration and growth in glioblastoma cells. Pharmacological inhibition of focal adhesion kinase (FAK) or downregulation of protein arginine methyltransferase 5 (PRMT5) blocks metabolic shift toward glycolysis and inhibits glioblastoma cell migration and invasion. These results support that integrin αvβ3 and osteopontin engagement plays an important role in promoting the metabolic shift toward glycolysis and inhibiting mitochondria oxidative phosphorylation in glioblastoma cells. The metabolic shift in cell energy metabolism is coupled to changes in migration, invasion, and growth, which are mediated by downstream FAK and PRMT5 in glioblastoma cells.