Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy

Abstract

ATB(0,+) [SLC6A14 (solute carrier family 6 member 14)] is an Na(+)/Cl(-)-coupled amino acid transporter whose expression is upregulated in cancer. 1-Methyltryptophan is an inducer of immune surveillance against tumour cells through its ability to inhibit indoleamine dioxygenase. In the present study, we investigated the role of ATB(0,+) in the uptake of 1-methyltryptophan as a potential mechanism for entry of this putative anticancer drug into tumour cells. These studies show that 1-methyltryptophan is a transportable substrate for ATB(0,+). The transport process is Na(+)/Cl(-)-dependent with an Na(+)/Cl(-)/1-methyltryptophan stoichiometry of 2:1:1. Evaluation of other derivatives of tryptophan has led to identification of alpha-methyltryptophan as a blocker, not a transportable substrate, for ATB(0,+). ATB(0,+) can transport 18 of the 20 proteinogenic amino acids. alpha-Methyltryptophan blocks the transport function of ATB(0,+) with an IC(50) value of approximately 250 muM under conditions simulating normal plasma concentrations of all these 18 amino acids. These results suggest that alpha-methyltryptophan may induce amino acid deprivation in cells which depend on the transporter for their amino acid nutrition. Screening of several mammary epithelial cell lines shows that ATB(0,+) is expressed robustly in some cancer cell lines, but not in all; in contrast, non-malignant cell lines do not express the transporter. Treatment of ATB(0,+)-positive tumour cells with alpha-methyltryptophan leads to suppression of their colony-forming ability, whereas ATB(0,+)-negative cell lines are not affected. The blockade of ATB(0,+) in these cells with alpha-methyltryptophan is associated with cell cycle arrest. These studies reveal the potential of ATB(0,+) as a drug target for cancer chemotherapy.

RETRACTION: Immunohistochemical and Functional Characterization of Peptide, Organic Cation, Neutral and Basic Amino Acid, and Monocarboxylate Drug Transporters in Human Ocular Tissues

“…L-Tryptophan is not an exclusive substrate for ATB 0,+ , and it also transported by L and y + L-type amino acid transporter system but is known to have higher binding affinity to ATB 0,+ than all other amino acids (Karunakaran et al, 2008). Karunakaran et al (2008) reported the inhibitory effect of a-methyl tryptophan, which is not transported by ATB 0,+ . L-lactic acid and , and L-tryptophan was higher than retina-to-sclera transport and significantly inhibited in the presence of the inhibitor cocktail, whereas there was no effect of inhibitors on the transport of phenylacetic acid.…”

“…Phenformin and cimetidine are more potent inhibitors of OCT than metformin; however, metformin was preferred since it does not interact with efflux transporters such as MDR and MRP (Pedersen et al, 2008). L-Tryptophan is not an exclusive substrate for ATB 0,+ , and it also transported by L and y + L-type amino acid transporter system but is known to have higher binding affinity to ATB 0,+ than all other amino acids (Karunakaran et al, 2008). Karunakaran et al (2008) reported the inhibitory effect of a-methyl tryptophan, which is not transported by ATB 0,+ .…”

Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

“…1). Pharmacologic blockade of SLC6A14 in tumor cells causes amino acid starvation, autophagy followed by apoptosis, suppression of mTOR and HIF1a signaling, and inhibition of tumor growth in vitro and in vivo (41,42). However, the upregulation of this transporter is not a common phenomenon in all cancers; for example, the transporter is not upregulated in estrogen receptor-negative breast cancer.…”

Differential Expression of Folate Receptor-Alpha, Sodium-Dependent Multivitamin Transporter, and Amino Acid Transporter (B(0, +)) in Human Retinoblastoma (Y-79) and Retinal Pigment Epithelial (ARPE-19) Cell Lines

“…The transporter can concentrate substrates 1000-fold more inside cells. 25 In addition to its amino acid transport, it can also transport carnitine, D-serine, NOS (nitric oxide synthase) inhibitors, conjugated drugs, and prodrugs. This property makes it unique among amino acid transporters.…”

“…ARPE-19 cells (passages [18][19][20][21][22][23][24][25] were cultured in DMEM/F-12 containing 10% heatinactivated fetal bovine serum, 15 mM HEPES, 29 mM sodium bicarbonate, penicillin (100 units/mL), and streptomycin (100 mg/mL). Cells were maintained in 75 cm 2 tissue culture flasks at 37°C, in a humidified atmosphere of 5% CO 2 and 90% relative humidity.…”