In the May 2017 issue of Molecular Cancer Research, White and colleagues reported that “Glutamine Transporters are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer” (1). In this article they suggested that the amino acid transporters SLC1A4/ASCT1 and SLC1A5/ASCT2 both regulate glutamine uptake in prostate cancer cells, driven by androgen receptor (AR) signaling. However, ASCT1 is not a glutamine transporter, and the authors neglected to reference previous studies that documented the importance of ASCT2 in prostate cancer, including its role in glutamine metabolism and cell growth. In particular, a previous study had suggested that both ASCT1 and ASCT2 were androgen regulated (2), which was confirmed in the White and colleagues' article. These previously published data used androgen receptor (AR) Chip-Seq data mining to show putative androgen response element–binding sites in an intron in ASCT1, and the last exon of ASCT2 (2). These data were strengthened by examining mRNA expression in patient samples before and after androgen deprivation therapy (ADT), showing a significant decrease in both ASCT1 and ASCT2 expression after ADT, and Western blot analysis revealing upregulated protein expression after dihydrotestosterone treatment (2).

In the White and colleagues' article, Table 1 showed significantly increased expression of ASCT1 and ASCT2 in prostate cancer versus benign patient samples. The ASCT2 data presented is identical to previously published data that was mined using Oncomine datasets (3). While the ASCT1 data in Table 1 is novel, it should be noted that a previous study had also shown significantly increased expression of ASCT1, but not ASCT2, in metastatic prostate cancer (2).

Of particular note, the siRNA studies of ASCT2 presented by White and colleagues have been previously published, using shRNA (3). This previous study not only used LNCaP cells to show the importance of ASCT2-mediated glutamine uptake on cell growth, but also used PC-3 cells in vitro and in vivo (3). The siRNA results were not discussed in the White and colleagues' article as merely being confirmatory of previous published work.

While it is important to note the primacy of these previous studies, subsequent to publication of the White and colleagues' manuscript, new data has emerged detailing substrate specificities for ASCT1 and ASCT2, which is of critical importance for the field. While the prevailing literature suggested that ASCT2, but not ASCT1, could transport glutamine (4), Scopelliti and colleagues have now definitively proven this (5). They described two residues present in the ASCT2 substrate–binding site that are required for glutamine binding and transport, and are not present in ASCT1. Of importance, ASCT1 does not mediate glutamine transport; however, mutation of these residues to the ASCT2 sequence conferred glutamine transport in ASCT1 (5). As such, the title of the White and colleagues' article is misleading, as only ASCT2 is a glutamine transporter. While it is clear that ASCT1 knockdown also reduced glutamine uptake and cell growth in the White and colleagues' cell-based assays, it is likely this is due to indirect effects on transport. This has been previously reported for ASCT2, where ASCT2 shRNA led to decreased leucine transport, despite it not being an ASCT2 transport substrate (6). In that study, it was thought that as LAT1/SLC7A5 is an amino acid exchanger of both glutamine and leucine, reduced intracellular glutamine levels from ASCT2 knockdown may result in lower leucine uptake/exchange through LAT1. In the White and colleagues' article, ASCT1 siRNA may be reducing ASCT2-mediated glutamine exchange through blocking intracellular levels of other ASCT substrates such as alanine, serine, cysteine, or threonine.

Overall, the White and colleagues' article makes some important additions to the literature, and confirms previous data showing the critical role of oncogenic pathways driving transport of extracellular amino acids into cancer cells, thereby fuelling cancer cell growth.

See the Response, p. 1811

R.M. Ryan reports receiving commercial research support and is a consultant/advisory board member for MetabloQ Pharmaceuticals. J. Holst is chief scientific officer and reports receiving other commercial research support from MetabloQ Pharmaceuticals.

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