Differences in accumulation and the transport mechanism of L- and D-methionine in high- and low-grade human glioma cells

Introduction: Although [S-methyl-11C]-labeled L-methionine and D-methionine (C-11-L-MET and C-11-D-MET) are useful radiotracers for positron emission tomography imaging of brain tumors, it is not known whether the accumulation and transport mechanisms underlying uptake of C-11-D-MET and C-11-L-MET are the same. C-11-L-MET is mainly taken up by the amino acid transport system L. We evaluated accumulation and the transport mechanism of D-MET in high- and low-grade human glioma cells in vitro. Methods: The expression of transport system genes in high- (A172 and T98G) and low-grade (SW1088 and Hs683) glioma cells was quantitatively analyzed. Accumulation of [S-methyl-H-3]-MET (H-3-L-MET) and [S-methyl-H-3)-D-MET (H-3-D-MET) in these cells was compared during 60 min of incubation. The transport mechanism of H-3-L-MET and H-3-D-MET was investigated by incubating the cells with these compounds and examining the effect of the inhibitors 2-amino-2-norbornane-carboxylic acid or alpha-(methylamino) isobutyric acid. Results: Absolute expression levels of system L and system alanine-serine-cysteine (ASC) in high-grade glioma cells were higher than in low-grade cells. In high-grade glioma cells, expression of system ASC genes was higher than that of system L genes. H-3-D-MET, which is transported by systems L and ASC, accumulated at higher levels than H-3-L-MET at all incubation times because H-3-D-MET is more sensitive to system ASC than H-3-L-MET. Conversely, in low-grade glioma cells with lower expression of system L and ASC, H-3-D-MET accumulated at higher levels than H-3-L-MET in early incubation times because H-3-D-MET may be more sensitive to system ASC than system L. Conclusion: H-3-D-MET was mainly transported by systems L and ASC and sensitive to system ASC, whereas H-3-L-MET was transported by system L in human glioma cells. In vitro, the accumulation of H-3-D-MET was significantly higher than that of H-3-L-MET during the entire incubation time in high-grade glioma cells, and in early incubation times in low-grade glioma cells. C) 2016 Elsevier Inc. All rights reserved.