Glioblastoma development in mouse brain: general reduction of OCTs and mislocalization of OCT3 transporter and subsequent uptake of ASP+ substrate to the nuclei.

Organic cation transporters (OCTs) were first found and then isolated from cultured glioma cells. When glioma cells are implanted into brain the fate of OCTs varies with time after implantation and transporter type. Here we report that OCT1, OCT2 and OCT3 immunofluorescence is significantly reduced over time in implanted GL261 glioma cells, during tumor development in the brain. By day 21 after glioma implantation, OCT1, OCT2 and OCT3 immunofluorescence was reduced more than 10-fold in the cytoplasm of glioma cells, while OCT3 immunofluorescence became concentrated in the nucleus. The well-known fluorescent substrate for OCT transporters, 4-(4-(dimethylamino)-styryl)-N-methylpyridinium iodide (ASP+), previously shown to accumulate in glioma-cell cytoplasm in in vivo slices, began to accumulate in the nucleus of these cells, but not in cytoplasm, after 21 days post-implantation. Considering this mislocalization phenomenon, and other literature on similar nuclear mislocalization of different transporters, receptors and channels in glioma cells, we suggest that it is one of the "omens" preceding the motility and aggressivity changes in glioma behavior.