ATB0,+ [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 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+/Cl−-dependent with an Na+/Cl−/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.
Skip Nav Destination
Article navigation
September 2008
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
August 27 2008
Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy
Senthil Karunakaran;
Senthil Karunakaran
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
Search for other works by this author on:
Nagavedi S. Umapathy;
Nagavedi S. Umapathy
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
Search for other works by this author on:
Muthusamy Thangaraju;
Muthusamy Thangaraju
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
Search for other works by this author on:
Takahiro Hatanaka;
Takahiro Hatanaka
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
Search for other works by this author on:
Shiro Itagaki;
Shiro Itagaki
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
Search for other works by this author on:
David H. Munn;
David H. Munn
†Immunotherapy Center, Medical College of Georgia, Augusta, GA 30912, U.S.A.
Search for other works by this author on:
Puttur D. Prasad;
Puttur D. Prasad
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
Search for other works by this author on:
Vadivel Ganapathy
Vadivel Ganapathy
1
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
1To whom correspondence should be addressed (email vganapat@mcg.edu).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
March 19 2008
Revision Received:
May 19 2008
Accepted:
June 03 2008
Accepted Manuscript online:
June 03 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 414 (3): 343–355.
Article history
Received:
March 19 2008
Revision Received:
May 19 2008
Accepted:
June 03 2008
Accepted Manuscript online:
June 03 2008
Citation
Senthil Karunakaran, Nagavedi S. Umapathy, Muthusamy Thangaraju, Takahiro Hatanaka, Shiro Itagaki, David H. Munn, Puttur D. Prasad, Vadivel Ganapathy; Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy. Biochem J 15 September 2008; 414 (3): 343–355. doi: https://doi.org/10.1042/BJ20080622
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.