Retracted: Superoxide‐dependent uptake of vitamin C in human glioma cells

• Published in: Journal of neurochemistry 2013-12, Vol.127 (6), p.793-804
• Main Authors: Rodríguez, Federico S., Salazar, Katterine A., Jara, Nery A., García‐Robles, María A, Pérez, Fernando, Ferrada, Luciano E., Martínez, Fernando, Nualart, Francisco J.
• Format: Article
• Language: English
• Subjects: glioblastoma; GLUT; microglia; SVCT2; vitamin C
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12365

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. 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) genera