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Specific transport of 3-fluoro-l-α-methyl-tyrosine by LAT1 explains its specificity to malignant tumors in imaging.

Wei L, Tominaga H, Ohgaki R, Wiriyasermkul P, Hagiwara K, Okuda S, Kaira K, Oriuchi N, Nagamori S, Kanai Y - Cancer Sci. (2016)

Bottom Line: Km of LAT1-mediated [14C]FAMT transport was 72.7 μM, similar to that for endogenous substrates.FAMT is highly specific to cancer-type amino acid transporter LAT1, which explains the cancer-specific accumulation of [18F]FAMT in PET.This, vice versa, further supports the cancer-specific expression of LAT1.

View Article: PubMed Central - PubMed

Affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan.

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Related in: MedlinePlus

[14C]FAMT transport by neutral amino acid transporters other than system L that transport aromatic amino acids. The uptakes of 50 μM l‐[14C]tyrosine (Tyr), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by TAT1 (a), the uptakes of 50 μM l‐[14C]leucine (Leu), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by B0AT1 (b), ATB0,+ (c), y+LAT1 (e) and y+LAT2 (f), and the uptakes of 50 μM l‐[14C]cystine (Cyst), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by b0,+ (d) were measured on the control oocytes (“−”) and the oocytes expressing each transporter (“+”). For the functional expression of b0,+ in (d), rBAT, an auxiliary subunit of system b0,+ transporter strongly inducing system b0,+ activity in Xenopus oocytes, was expressed in Xenopus oocytes, therefore, the induced system b0,+ activity was not that of human but of Xenopus although human rBAT was expressed.16l‐[14C]Tyrosine and l‐[14C]cystine were used as typical substrates of TAT1 and b0,+, respectively. l‐[14C]Leucine was used as a typical substrate of B0AT1, ATB0,+, y+LAT1 and y+LAT2. Na+‐free uptake buffer was used for TAT1 and b0,+, whereas ND96 solution was used for the others. Uptakes were measured for 30 min for B0AT1 and for 15 min for the others. Uptake rates were expressed as mean ± SEM (n = 5–10). *P < 0.05; n.s., not significant.
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cas12878-fig-0002: [14C]FAMT transport by neutral amino acid transporters other than system L that transport aromatic amino acids. The uptakes of 50 μM l‐[14C]tyrosine (Tyr), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by TAT1 (a), the uptakes of 50 μM l‐[14C]leucine (Leu), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by B0AT1 (b), ATB0,+ (c), y+LAT1 (e) and y+LAT2 (f), and the uptakes of 50 μM l‐[14C]cystine (Cyst), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by b0,+ (d) were measured on the control oocytes (“−”) and the oocytes expressing each transporter (“+”). For the functional expression of b0,+ in (d), rBAT, an auxiliary subunit of system b0,+ transporter strongly inducing system b0,+ activity in Xenopus oocytes, was expressed in Xenopus oocytes, therefore, the induced system b0,+ activity was not that of human but of Xenopus although human rBAT was expressed.16l‐[14C]Tyrosine and l‐[14C]cystine were used as typical substrates of TAT1 and b0,+, respectively. l‐[14C]Leucine was used as a typical substrate of B0AT1, ATB0,+, y+LAT1 and y+LAT2. Na+‐free uptake buffer was used for TAT1 and b0,+, whereas ND96 solution was used for the others. Uptakes were measured for 30 min for B0AT1 and for 15 min for the others. Uptake rates were expressed as mean ± SEM (n = 5–10). *P < 0.05; n.s., not significant.

Mentions: Among the transporters from system L for large neutral amino acids, LAT1‐expressing oocytes exhibited a high level of [14C]FAMT uptake compared with control oocytes (Fig. 1a). Its transport rate was comparable to that of l‐[14C]leucine, a typical substrate of LAT1. LAT2, LAT3 and LAT4 did not mediate [14C]FAMT transport (Fig. 1b–d). In contrast, l‐[14C]methionine was transported by all the system L transporters (Fig. 1). Other amino acid transporters transporting aromatic amino acids, TAT1, B0AT1, ATB0,+, b0,+, y+LAT1 and y+LAT2, did not transport [14C]FAMT, whereas these transporters except TAT1 transported l‐[14C]methionine (Fig. 2). The transporters for small neutral amino acids, ASCT1, ASCT2, SNAT1, SNAT2, SNAT3, SNAT4 and SNAT5, did not transport [14C]FAMT, whereas l‐[14C]methionine was transported by all except ASCT1 (Fig. S2). The results on the amino acid transporters are summarized in Table 1.


Specific transport of 3-fluoro-l-α-methyl-tyrosine by LAT1 explains its specificity to malignant tumors in imaging.

Wei L, Tominaga H, Ohgaki R, Wiriyasermkul P, Hagiwara K, Okuda S, Kaira K, Oriuchi N, Nagamori S, Kanai Y - Cancer Sci. (2016)

[14C]FAMT transport by neutral amino acid transporters other than system L that transport aromatic amino acids. The uptakes of 50 μM l‐[14C]tyrosine (Tyr), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by TAT1 (a), the uptakes of 50 μM l‐[14C]leucine (Leu), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by B0AT1 (b), ATB0,+ (c), y+LAT1 (e) and y+LAT2 (f), and the uptakes of 50 μM l‐[14C]cystine (Cyst), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by b0,+ (d) were measured on the control oocytes (“−”) and the oocytes expressing each transporter (“+”). For the functional expression of b0,+ in (d), rBAT, an auxiliary subunit of system b0,+ transporter strongly inducing system b0,+ activity in Xenopus oocytes, was expressed in Xenopus oocytes, therefore, the induced system b0,+ activity was not that of human but of Xenopus although human rBAT was expressed.16l‐[14C]Tyrosine and l‐[14C]cystine were used as typical substrates of TAT1 and b0,+, respectively. l‐[14C]Leucine was used as a typical substrate of B0AT1, ATB0,+, y+LAT1 and y+LAT2. Na+‐free uptake buffer was used for TAT1 and b0,+, whereas ND96 solution was used for the others. Uptakes were measured for 30 min for B0AT1 and for 15 min for the others. Uptake rates were expressed as mean ± SEM (n = 5–10). *P < 0.05; n.s., not significant.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4814262&req=5

cas12878-fig-0002: [14C]FAMT transport by neutral amino acid transporters other than system L that transport aromatic amino acids. The uptakes of 50 μM l‐[14C]tyrosine (Tyr), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by TAT1 (a), the uptakes of 50 μM l‐[14C]leucine (Leu), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by B0AT1 (b), ATB0,+ (c), y+LAT1 (e) and y+LAT2 (f), and the uptakes of 50 μM l‐[14C]cystine (Cyst), [14C]FAMT (FAMT) and l‐[14C]methionine (Met) by b0,+ (d) were measured on the control oocytes (“−”) and the oocytes expressing each transporter (“+”). For the functional expression of b0,+ in (d), rBAT, an auxiliary subunit of system b0,+ transporter strongly inducing system b0,+ activity in Xenopus oocytes, was expressed in Xenopus oocytes, therefore, the induced system b0,+ activity was not that of human but of Xenopus although human rBAT was expressed.16l‐[14C]Tyrosine and l‐[14C]cystine were used as typical substrates of TAT1 and b0,+, respectively. l‐[14C]Leucine was used as a typical substrate of B0AT1, ATB0,+, y+LAT1 and y+LAT2. Na+‐free uptake buffer was used for TAT1 and b0,+, whereas ND96 solution was used for the others. Uptakes were measured for 30 min for B0AT1 and for 15 min for the others. Uptake rates were expressed as mean ± SEM (n = 5–10). *P < 0.05; n.s., not significant.
Mentions: Among the transporters from system L for large neutral amino acids, LAT1‐expressing oocytes exhibited a high level of [14C]FAMT uptake compared with control oocytes (Fig. 1a). Its transport rate was comparable to that of l‐[14C]leucine, a typical substrate of LAT1. LAT2, LAT3 and LAT4 did not mediate [14C]FAMT transport (Fig. 1b–d). In contrast, l‐[14C]methionine was transported by all the system L transporters (Fig. 1). Other amino acid transporters transporting aromatic amino acids, TAT1, B0AT1, ATB0,+, b0,+, y+LAT1 and y+LAT2, did not transport [14C]FAMT, whereas these transporters except TAT1 transported l‐[14C]methionine (Fig. 2). The transporters for small neutral amino acids, ASCT1, ASCT2, SNAT1, SNAT2, SNAT3, SNAT4 and SNAT5, did not transport [14C]FAMT, whereas l‐[14C]methionine was transported by all except ASCT1 (Fig. S2). The results on the amino acid transporters are summarized in Table 1.

Bottom Line: Km of LAT1-mediated [14C]FAMT transport was 72.7 μM, similar to that for endogenous substrates.FAMT is highly specific to cancer-type amino acid transporter LAT1, which explains the cancer-specific accumulation of [18F]FAMT in PET.This, vice versa, further supports the cancer-specific expression of LAT1.

View Article: PubMed Central - PubMed

Affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan.

Show MeSH
Related in: MedlinePlus