Boronophenylalanine, a boron delivery agent for boron neutron capture therapy, is transported by ATB0,+, LAT1 and LAT2.
Bottom Line: Among aromatic amino acid transporters, ATB(0,+), LAT1 and LAT2 were found to transport BPA with Km values of 137.4 ± 11.7, 20.3 ± 0.8 and 88.3 ± 5.6 μM, respectively.Uptake experiments in cancer cell lines revealed that the LAT1 protein amount was the major determinant of BPA uptake at 100 μM, whereas the contribution of ATB(0,+) became significant at 1000 μM, accounting for 20-25% of the total BPA uptake in MCF-7 breast cancer cells.ATB(0,+), LAT1 and LAT2 transport BPA at affinities comparable with their endogenous substrates, suggesting that they could mediate effective BPA uptake in vivo.
Affiliation: Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan.Show MeSH
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Mentions: ATB0,+ has a lower affinity to BPA than LAT1 (Table2). Thus, ATB0,+ is proposed to work at higher BPA concentrations. Consistent with this, a significant Na+-dependent uptake of BPA was observed at 1000 μM in MCF-7 cells (Fig.6a). To reduce the contribution of LAT1 to BPA uptake in MCF-7 cells, the LAT1 expression was silenced by RNA interference. Treatment of MCF-7 cells with siRNAs depleted the LAT1 protein amount to ∽20% (Fig.6b). Among the siRNAs tested, control siRNAs and LAT1 siRNAs had a similar impact on the LAT1 protein amount (Fig.6b) and BPA uptake (Fig. S2). After LAT1 was knocked down in 1000 μM BPA, the residual component was further decreased by removing Na+ and also inhibited by lysine, a high-affinity substrate of ATB0,+ (Km, ∽100 μM)21 but not interactive with LAT112 (Fig.6c). This Na+-dependent and lysine-inhibitable component is proposed to be mediated by ATB0,+. Such component was only found at 1000 μM, accounting for at least 20–25% of the total BPA uptake (Fig.6c). In 100 μM of BPA, the residual component after LAT1 knockdown was not dependent on Na+ (Fig.6c).
Affiliation: Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan.