The SLC38A5/SNAT5 amino acid transporter: from pathophysiology to pro-cancer roles in the tumor microenvironment

Abstract

SLC38A5/SNAT5 is a system N transporter that can mediate net inward or outward transmembrane fluxes of neutral amino acids coupled with Na+ (symport) and H+ (antiport). Its preferential substrates are amino acids with side chains containing amide (glutamine, and asparagine) or imidazole (histidine) groups, but also serine, glycine and alanine are transported by the carrier. Expressed in the pancreas, intestinal tract, brain, liver, bone marrow, and placenta, it is regulated at mRNA and protein levels by mTORC1 and WNT/β-catenin pathways, and it is sensitive to pH, nutritional stress, inflammation, and hypoxia. SNAT5 expression has been found to be altered in pathological conditions such as chronic inflammatory diseases, gestational complications, chronic metabolic acidosis and malnutrition. Growing experimental evidence shows that SNAT5 is overexpressed in several types of cancer cells. Moreover, recently published results indicate that SNAT5 expression in stromal cells can support the metabolic exchanges occurring in the tumor microenvironment of asparagine-auxotroph tumors. We review the functional role of the SNAT5 transporter in pathophysiology and propose that, due to its peculiar operational and regulatory features, SNAT5 may play important pro-cancer roles when expressed either in neoplastic or in stromal cells of glutamine-auxotroph tumors.

GLS and GOT2 as prognostic biomarkers associated with dendritic cell and immunotherapy response in breast cancer

“…There was not glutamine metabolism related reports about F13A1, NOS3, GFPT2, TGM2 and SLC7A7 genes. SLC38A5 is reported as a amino acid transporter shuttled amino acids (including glutamine) across cell member but not the glutamine specific transporter [ [55] , [56] , [57] ]. Both GLS and GOT2 were essential genes to glutamine metabolism [ 28 , 36 , 37 ].…”

Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP‐ALL cell survival and a potential therapeutic target

“…With respect to ASCT2, the pro‐tumoral role of SNAT5 is much less characterized and is emerging only in the last few years, in parallel with a renewed interest in Asn 46–48 . However, the transporter is highly regulated, is a target of Myc and is overexpressed in different cancer models 49–51 …”