Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) 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+/Cl--coupled amino acid transporter whose expression is up-regulated in cancer. 1-Methyltryptophan is an inducer of immune surveillance against tumour Cells through its ability to inhibit indoleamine dioxygenase. fit 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 IC50 value of similar to 250 mu M under conditions simulating normal plasma concentrations of all these 18 amino acids. These results Suggest that a-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 a-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.