SLC6A14 (ATB 0,+) protein, a highly concentrative and broad specific amino acid transporter, is a novel and effective drug target for treatment of estrogen receptor-positive breast cancer

Senthil Karunakaran, Sabarish Ramachandran, Veena Coothankandaswamy, Selvakumar Elangovan, Ellappan Babu, Sudharsan Periyasamy-Thandavan, Ashish Gurav, Jaya P. Gnanaprakasam, Nagendra Singh, Patricia V. Schoenlein, Puttur D. Prasad, Muthusamy Thangaraju, Vadivel Ganapathy

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

SLC6A14, also known as ATB 0,+, is an amino acid transporter with unique characteristics. It transports 18 of the 20 proteinogenic amino acids. However, this transporter is expressed only at low levels in normal tissues. Here, we show that the transporter is up-regulated specifically in estrogen receptor (ER)- positive breast cancer, demonstrable with primary human breast cancer tissues and human breast cancer cell lines. SLC6A14 is an estrogen/ER target. The transport features of SLC6A14 include concentrative transport of leucine (an activator of mTOR), glutamine (an essential amino acid for nucleotide biosynthesis and substrate for glutaminolysis), and arginine (an essential amino acid for tumor cells), suggesting that ER-positive breast cancer cells up-regulate SLC6A14 to meet their increased demand for these amino acids. Consequently, treatment of ER-positive breast cancer cells in vitro with α-methyl- DL-tryptophan (α-MT), a selective blocker of SLC6A14, induces amino acid deprivation, inhibits mTOR, and activates autophagy. Prolongation of the treatment with α-MT causes apoptosis. Addition of an autophagy inhibitor (3-methyladenine) during α-MT treatment also induces apoptosis. These effects of α-MT are specific to ER-positive breast cancer cells, which express the transporter. The ability of α-MT to cause amino acid deprivation is significantly attenuated in MCF-7 cells, an ER-positive breast cancer cell line, when SLC6A14 is silenced with shRNA. In mouse xenograft studies, α-MT by itself is able to reduce the growth of the ER-positive ZR-75-1 breast cancer cells. These studies identify SLC6A14 as a novel and effective drug target for the treatment of ER-positive breast cancer.

Original languageEnglish (US)
Pages (from-to)31830-31838
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number36
DOIs
StatePublished - Sep 9 2011

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Amino Acid Transport Systems
Estrogen Receptors
Breast Neoplasms
Cells
Pharmaceutical Preparations
Proteins
Amino Acids
Essential Amino Acids
Autophagy
Tissue
Apoptosis
Cell Line
Biosynthesis
Glutamine
MCF-7 Cells
Heterografts
Leucine
Tryptophan
Small Interfering RNA
Arginine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

SLC6A14 (ATB 0,+) protein, a highly concentrative and broad specific amino acid transporter, is a novel and effective drug target for treatment of estrogen receptor-positive breast cancer. / Karunakaran, Senthil; Ramachandran, Sabarish; Coothankandaswamy, Veena; Elangovan, Selvakumar; Babu, Ellappan; Periyasamy-Thandavan, Sudharsan; Gurav, Ashish; Gnanaprakasam, Jaya P.; Singh, Nagendra; Schoenlein, Patricia V.; Prasad, Puttur D.; Thangaraju, Muthusamy; Ganapathy, Vadivel.

In: Journal of Biological Chemistry, Vol. 286, No. 36, 09.09.2011, p. 31830-31838.

Research output: Contribution to journalArticle

Karunakaran, Senthil ; Ramachandran, Sabarish ; Coothankandaswamy, Veena ; Elangovan, Selvakumar ; Babu, Ellappan ; Periyasamy-Thandavan, Sudharsan ; Gurav, Ashish ; Gnanaprakasam, Jaya P. ; Singh, Nagendra ; Schoenlein, Patricia V. ; Prasad, Puttur D. ; Thangaraju, Muthusamy ; Ganapathy, Vadivel. / SLC6A14 (ATB 0,+) protein, a highly concentrative and broad specific amino acid transporter, is a novel and effective drug target for treatment of estrogen receptor-positive breast cancer. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 36. pp. 31830-31838.
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abstract = "SLC6A14, also known as ATB 0,+, is an amino acid transporter with unique characteristics. It transports 18 of the 20 proteinogenic amino acids. However, this transporter is expressed only at low levels in normal tissues. Here, we show that the transporter is up-regulated specifically in estrogen receptor (ER)- positive breast cancer, demonstrable with primary human breast cancer tissues and human breast cancer cell lines. SLC6A14 is an estrogen/ER target. The transport features of SLC6A14 include concentrative transport of leucine (an activator of mTOR), glutamine (an essential amino acid for nucleotide biosynthesis and substrate for glutaminolysis), and arginine (an essential amino acid for tumor cells), suggesting that ER-positive breast cancer cells up-regulate SLC6A14 to meet their increased demand for these amino acids. Consequently, treatment of ER-positive breast cancer cells in vitro with α-methyl- DL-tryptophan (α-MT), a selective blocker of SLC6A14, induces amino acid deprivation, inhibits mTOR, and activates autophagy. Prolongation of the treatment with α-MT causes apoptosis. Addition of an autophagy inhibitor (3-methyladenine) during α-MT treatment also induces apoptosis. These effects of α-MT are specific to ER-positive breast cancer cells, which express the transporter. The ability of α-MT to cause amino acid deprivation is significantly attenuated in MCF-7 cells, an ER-positive breast cancer cell line, when SLC6A14 is silenced with shRNA. In mouse xenograft studies, α-MT by itself is able to reduce the growth of the ER-positive ZR-75-1 breast cancer cells. These studies identify SLC6A14 as a novel and effective drug target for the treatment of ER-positive breast cancer.",
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AU - Coothankandaswamy, Veena

AU - Elangovan, Selvakumar

AU - Babu, Ellappan

AU - Periyasamy-Thandavan, Sudharsan

AU - Gurav, Ashish

AU - Gnanaprakasam, Jaya P.

AU - Singh, Nagendra

AU - Schoenlein, Patricia V.

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