Regulation and Function of Aquaporin-1 in Glioma Cells

Abstract

Glioblastoma multiformes (GBMs) express increased aquaporin (AQP) 1 compared to normal brain. AQPs may contribute to edema, cell motility, shuttling of H2O and H+ from intracellular to extracellular space. We sought to gain insight into AQPs function in GBM. In cultured 9L gliosarcoma cells, AQPs expression was induced by dexamethasone, platelet-derived growth factor, NaCl, hypoxia, D-glucose (but not L-glucose), fructose. Induction of AQPs expression correlated with the level of glycolysis, maximized by increasing medium D-glucose or fructose and decreasing O2, was quantified by measuring lactate dehydrogenase (LDH) activity and medium lactate concentration. Upregulation of the protease cathepsin B was also observed in 9L cells cultured under glycolytic conditions. Immunohistochemical staining of human GBM specimens revealed increased coincident expression of AQPs, LDH, cathepsin B in glioma cells associated with blood vessels at the tumor periphery. GBMs are known to exhibit aerobic glycolysis. Increased glucose metabolism at the tumor periphery may provide a scenario by which upregulation of AQPs, LDH, cathepsin B contributes to acidification of the extracellular milieu and to invasive potential of glioma cells in perivascular space. The specific upregulation and metabolic consequences of increased AQPs in gliomas may provide a therapeutic target, both as a cell surface marker and as a functional intervention.

Keywords

• Aquaporin
• cathepsin B
• glioma
• glycolysis
• invasion