title: Superoxide-dependent uptake of vitamin C in human glioma cells.
abstract: Glioblastomas are lethal brain tumors that resist current cytostatic therapies. Vitamin C may antagonize the effects of reactive oxygen species (ROS) generating therapies; however, it is often used to reduce therapy-related side effects despite its effects on therapy or tumor growth. Because the mechanisms of vitamin C uptake in gliomas are currently unknown, we evaluated the expression of the sodium-vitamin C cotransporter (SVCT) and facilitative hexose transporter (GLUT) families in human glioma cells. In addition, as microglial cells can greatly infiltrate high-grade gliomas (constituting up to 45% of cells in glioblastomas), the effect of TC620 glioma cell interactions with microglial-like HL60 cells on vitamin C uptake (Bystander effect) was determined. Although glioma cells expressed high levels of the SVCT isoform-2 (SVCT2), low functional activity, intracellular localization and the expression of the dominant-negative isoform (dnSVCT2) were observed. The increased glucose metabolic activity of glioma cells was evident by the high 2-Deoxy-d-glucose and dehydroascorbic acid (DHA) uptake rates through the GLUT isoform-1 (GLUT1), the main DHA transporter in glioblastoma. Co-culture of glioma cells and activated microglial-like HL60 cells resulted in extracellular ascorbic acid oxidation and high DHA uptake by glioma cells. This Bystander effect may explain the high antioxidative potential observed in high-grade gliomas. This study strongly suggests that the Bystander effect, that is, glioma cell interaction with oxidant-producing microglia, could be an important mechanism for glioma vitamin C loading in the absence of functional sodium-vitamin C cotransporter 2 (SVCT2) expression. The high cellular vitamin C load in glioma cells results from a high uptake of extracellular dehydroascorbic acid (DHA) generated by neighboring microglia. This Bystander effect may explain the high antioxidative potential observed in high-grade gliomas, considering that high-grade gliomas may be the only neoplasm where oxidant-producing microglia can almost equal the number of tumor cells.
authors.affiliation: Laboratory of Neurobiology and Stem Cells, Center for Advanced Microscopy CMA BIOBIO, University of Concepcion, Concepcion, Chile.
authors.forename: Federico S
authors.initials: FS
authors.lastname: Rodríguez
authors.forename: Katterine A
authors.initials: KA
authors.lastname: Salazar
authors.forename: Nery A
authors.initials: NA
authors.lastname: Jara
authors.forename: María A
authors.initials: MA
authors.lastname: García-Robles
authors.forename: Fernando
authors.initials: F
authors.lastname: Pérez
authors.forename: Luciano E
authors.initials: LE
authors.lastname: Ferrada
authors.forename: Fernando
authors.initials: F
authors.lastname: Martínez
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Nualart
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D001205:Ascorbic Acid / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D024201:Bystander Effect; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003683:Dehydroascorbic Acid / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D005910:Glioma / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D017628:Microglia / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060347:Sodium-Coupled Vitamin C Transporters / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D051272:Glucose Transporter Type 1; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D060347:Sodium-Coupled Vitamin C Transporters; D013481:Superoxides; D003847:Deoxyglucose; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid
keywords: GLUT; SVCT2; glioblastoma; microglia; vitamin C