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 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.
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.
Senthil
S
Karunakaran
Nagavedi S
NS
Umapathy
Muthusamy
M
Thangaraju
Takahiro
T
Hatanaka
Shiro
S
Itagaki
David H
DH
Munn
Puttur D
PD
Prasad
Vadivel
V
Ganapathy
D026905:Amino Acid Transport Systems / Q000378:metabolism; D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014982:Xenopus laevis
D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral; D000970:Antineoplastic Agents; D027283:Large Neutral Amino Acid-Transporter 1; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C503995:SLC6A14 protein, human; C532353:Slc6A14 protein, mouse; C020774:alpha-methyltryptophan; D014364:Tryptophan; C525396:1-methyltryptophan