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

ATB 0,ϩ (amino acid transporter responsible for the activity of system B 0,ϩ ) was named "B 0,ϩ " to indicate its broad substrate selectivity (denoted by "B"), accepting neutral (denoted by "0") and cationic (denoted by "ϩ") amino acids as substrates (1, 2). Its transport function is coupled to a Na ϩ gradient, a Cl Ϫ gradient, and membrane potential. ATB 0,ϩ is identified as SLC6A14 according to the Human Genome Organization nomenclature. This transporter has potential for delivery of a wide variety of drugs and prodrugs into cells (3-7). The substrate selectivity of SLC6A14 is interesting (1, 2). It transports all essential amino acids. The only excluded amino acids are glutamate and aspartate, which are nonessential. It also transports glutamine (an important precursor for nucleotide synthesis) and arginine (an amino acid essential for tumor growth). However, the transporter is expressed only at low levels in normal tissues. Tumor cells have an increased requirement for essential amino acids as well as glutamine and arginine to support their rapid growth. Essential amino acids are obligatory for protein synthesis. Leucine, an essential amino acid, is also a potent activator of mTOR (mammalian target of rapamycin) (8). Certain tumor cells metabolize glutamine at a rate far exceeding the requirement for protein and nucleotide synthesis, a phenomenon known as "glutamine addiction" (9 -11). Glutamine metabolism through a set of biochemical reactions called "glutaminolysis" provides a carbon source for tumor cells, thereby sparing glucose-derived carbon for the synthesis of lipids and other essential biomolecules. Arginine is essential for several types of cancer due to lack of the arginine-synthesizing enzyme argininosuccinate synthetase (12, 13). On the basis of these findings, we hypothesized that the expression of SLC6A14 may be up-regulated in cancer to meet the increasing demand for all essential amino acids as well as glutamine and arginine. In support of this hypothesis, past studies from our laboratory have shown that SLC6A14 is up-regulated in colon cancer (14) and cervical cancer (15). The transporter is also up-regulated in breast cancer cell lines, but interestingly only in estrogen receptor (ER) 2 -positive cell lines (16). Furthermore, we showed that blockade of SLC6A14 in ER-positive breast cancer cells by treatment with a selective blocker (␣-methyl-DLtryptophan (␣-MT)) starved the cells of glutamine, arginine, and essential amino acids, decreased cell proliferation, and caused apoptotic cell death (16). In the present study, we investigated the expression of SLC6A14 in primary breast cancer * This work was supported, in whole or in part, by National Institutes of Health Grant CA152396. 1 To whom correspondence should be addressed. E-mail: vganapat@ georgiahealth.edu.2 The abbreviations used are: ER, estrogen receptor; ␣-MT, ␣-methyl-DL-tryptophan; CHOP, CCAAT/enhancer-binding protein homologous protein; 3-MA, 3-methyladenine.

Genetic Disruption of the Multifunctional CD98/LAT1 Complex Demonstrates the Key Role of Essential Amino Acid Transport in the Control of mTORC1 and Tumor Growth

“…First, we tested the possibility that CD98 disruption could have induced another transporter capable to compensate for the lack of EAA transport by LAT1. A good candidate was SLC6A14, which transports all neutral AA (30). LAT1 knockout dramatically reduces cell proliferation, whereas CD98 ablation has no effect.…”

Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

“…1). Pharmacologic blockade of SLC6A14 in tumor cells causes amino acid starvation, autophagy followed by apoptosis, suppression of mTOR and HIF1a signaling, and inhibition of tumor growth in vitro and in vivo (41,42). However, the upregulation of this transporter is not a common phenomenon in all cancers; for example, the transporter is not upregulated in estrogen receptor-negative breast cancer.…”

Amino Acid Transporters in Drug Discovery

“…LAT1 and LAT2 are widely expressed (brain, ovary, testis, placenta, spleen, colon, blood-brain barrier, fetal liver, activated lymphocytes, skeletal muscle, heart, lung, thymus and kidney (Kanai et al, 1998;Yoon et al, 2005). In polarized epithelia cells, they are mainly localized at the basolateral membranes.…”

“…LAT1 and LAT2 are classified in this second subgroup. Their cDNAs have been isolated and identified in 1998 and in 1999 (Kanai et al, 1998;Pineda et al, 1999;Prasad et al, 1999;Segawa et al, 1999).…”