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

Senthil Karunakaran, Umapathy N Siddaramappa, Muthusamy Thangaraju, Takahiro Hatanaka, Shiro Itagaki, David H Munn, Puttur D Prasad, Vadivel Ganapathy

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

ATB0,+ [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 ATB0,+ 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 ATB0,-. 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 ATB0,+. ATB0,+ can transport 18 of the 20 proteinogenic amino acids. α-Methyltryptophan blocks the transport function of ATB0,+ 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 ATB0,+ 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 ATB0,--positive tumour cells with α-methyltryptophan leads to suppression of their colony-forming ability, whereas ATB0,+-negative cell lines are not affected. The blockade of ATB0,+ in these cells with α-methyltryptophan is associated with cell cycle arrest. These studies reveal the potential of ATB0,+ as a drug target for cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)343-355
Number of pages13
JournalBiochemical Journal
Volume414
Issue number3
DOIs
StatePublished - Sep 15 2008

Keywords

  • 1-methyltryptophan
  • Amino acid nutrition
  • Cancer therapy
  • Solute carrier family 6 member 14 (SLC6A14)
  • Transport blocker
  • Tumour cell growth

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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