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

57 Citations (Scopus)

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

Fingerprint

Chemotherapy
Tryptophan
Cells
Derivatives
Drug Therapy
Pharmaceutical Preparations
Amino Acid Transport Systems
Cell Line
Neoplasms
Aptitude
Tumors
Amino Acids
Dioxygenases
Cell Cycle Checkpoints
Inhibitory Concentration 50
Substrates
Nutrition
Stoichiometry
Breast
Epithelial Cells

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

Cite this

Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy. / Karunakaran, Senthil; Siddaramappa, Umapathy N; Thangaraju, Muthusamy; Hatanaka, Takahiro; Itagaki, Shiro; Munn, David H; Prasad, Puttur D; Ganapathy, Vadivel.

In: Biochemical Journal, Vol. 414, No. 3, 15.09.2008, p. 343-355.

Research output: Contribution to journalArticle

@article{0ce333acfed84aa0a840623e0f5fa671,
title = "Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy",
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.",
keywords = "1-methyltryptophan, Amino acid nutrition, Cancer therapy, Solute carrier family 6 member 14 (SLC6A14), Transport blocker, Tumour cell growth",
author = "Senthil Karunakaran and Siddaramappa, {Umapathy N} and Muthusamy Thangaraju and Takahiro Hatanaka and Shiro Itagaki and Munn, {David H} and Prasad, {Puttur D} and Vadivel Ganapathy",
year = "2008",
month = "9",
day = "15",
doi = "10.1042/BJ20080622",
language = "English (US)",
volume = "414",
pages = "343--355",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "3",

}

TY - JOUR

T1 - Interaction of tryptophan derivatives with SLC6A14 (ATB0,+) reveals the potential of the transporter as a drug target for cancer chemotherapy

AU - Karunakaran, Senthil

AU - Siddaramappa, Umapathy N

AU - Thangaraju, Muthusamy

AU - Hatanaka, Takahiro

AU - Itagaki, Shiro

AU - Munn, David H

AU - Prasad, Puttur D

AU - Ganapathy, Vadivel

PY - 2008/9/15

Y1 - 2008/9/15

N2 - 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.

AB - 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.

KW - 1-methyltryptophan

KW - Amino acid nutrition

KW - Cancer therapy

KW - Solute carrier family 6 member 14 (SLC6A14)

KW - Transport blocker

KW - Tumour cell growth

UR - http://www.scopus.com/inward/record.url?scp=52449118755&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=52449118755&partnerID=8YFLogxK

U2 - 10.1042/BJ20080622

DO - 10.1042/BJ20080622

M3 - Article

C2 - 18522536

AN - SCOPUS:52449118755

VL - 414

SP - 343

EP - 355

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 3

ER -