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

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  • Additional Information
    • Source:
      Publisher: Published by Portland Press on behalf of the Biochemical Society Country of Publication: England NLM ID: 2984726R Publication Model: Print Cited Medium: Internet ISSN: 1470-8728 (Electronic) Linking ISSN: 02646021 NLM ISO Abbreviation: Biochem J Subsets: MEDLINE
    • Publication Information:
      Original Publication: London, UK : Published by Portland Press on behalf of the Biochemical Society
    • Subject Terms:
      Amino Acid Transport Systems, Neutral/*antagonists & inhibitors ; Antineoplastic Agents/*pharmacology ; Tryptophan/*analogs & derivatives; Amino Acid Transport Systems/metabolism ; Amino Acid Transport Systems, Neutral/genetics ; Amino Acid Transport Systems, Neutral/metabolism ; Animals ; Antineoplastic Agents/therapeutic use ; Biological Transport, Active/drug effects ; Cell Line ; Cell Line, Tumor ; Humans ; Large Neutral Amino Acid-Transporter 1/genetics ; Large Neutral Amino Acid-Transporter 1/metabolism ; Mice ; Oocytes/metabolism ; Plasma Membrane Neurotransmitter Transport Proteins/metabolism ; Tryptophan/metabolism ; Tryptophan/pharmacology ; Xenopus laevis
    • 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.
    • Accession Number:
      0 (Amino Acid Transport Systems)
      0 (Amino Acid Transport Systems, Neutral)
      0 (Antineoplastic Agents)
      0 (Large Neutral Amino Acid-Transporter 1)
      0 (Plasma Membrane Neurotransmitter Transport Proteins)
      0 (SLC6A14 protein, human)
      0 (Slc6A14 protein, mouse)
      13510-08-2 (alpha-methyltryptophan)
      8DUH1N11BX (Tryptophan)
      XD0FY1J13B (1-methyltryptophan)
    • Publication Date:
      Date Created: 20080605 Date Completed: 20081021 Latest Revision: 20190109
    • Publication Date:
      20240829
    • Accession Number:
      10.1042/BJ20080622
    • Accession Number:
      18522536