title: 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.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
authors.forename: Senthil
authors.initials: S
authors.lastname: Karunakaran
authors.forename: Sabarish
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Veena
authors.initials: V
authors.lastname: Coothankandaswamy
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Elangovan
authors.forename: Ellappan
authors.initials: E
authors.lastname: Babu
authors.forename: Sudharsan
authors.initials: S
authors.lastname: Periyasamy-Thandavan
authors.forename: Ashish
authors.initials: A
authors.lastname: Gurav
authors.forename: Jaya P
authors.initials: JP
authors.lastname: Gnanaprakasam
authors.forename: Nagendra
authors.initials: N
authors.lastname: Singh
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Schoenlein
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D011960:Receptors, Estrogen; D014183:Transplantation, Heterologous; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral; D011960:Receptors, Estrogen; C503995:SLC6A14 protein, human; D014364:Tryptophan