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SLC6A14 (ATB0,+) 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. | LitMetric

AI Article Synopsis

  • - SLC6A14, an amino acid transporter, is primarily found in low levels in normal tissues but is significantly up-regulated in estrogen receptor-positive breast cancer, which helps these cancer cells meet their increased amino acid needs for growth.
  • - The selective blocker α-methyl-DL-tryptophan (α-MT) induces amino acid deprivation in ER-positive breast cancer cells, leading to inhibited mTOR activity, activated autophagy, and eventually apoptosis with prolonged treatment.
  • - In mouse studies, α-MT effectively reduces the growth of ER-positive breast cancer, showcasing SLC6A14 as a promising drug target for treating this specific type of cancer.

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173074PMC
http://dx.doi.org/10.1074/jbc.M111.229518DOI Listing

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