Interaction of tryptophan derivatives with SLC6A14 (ATB^0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy

ATB^0,+ [SLC6A14 (solute carrier family 6 member 14)] is an Na⁺/ C1^--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⁺/C1^--dependent with an Na⁺/C1^-/ 1-methyltryptophan stoichiometry of 2:1:1. Evaluation of other derivatives of tryptophan has led to identification of α-methyltryptophan as a blocker, not a transportable substrate, for ATB^0,+. ATB^0,+ can transport 18 of the 20 proteinogenic amino acids. α-Methyltryptophan blocks the transport function of ATB^0,+ with an IC₅₀ value of ∼ 250 μM under conditions simulating normal plasma concentrations of all these 18 amino acids. These results suggest that α-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 α-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 α-methyltryptophan is associated with cell cycle arrest. These studies reveal the potential of ATB^0,+ as a drug target for cancer chemotherapy.