Expression and function of SLC38A5, an amino acid-coupled Na+/H+ exchanger, in triple-negative breast cancer and its relevance to macropinocytosis.

Metabolic reprogramming in cancer cells necessitates increased amino acid uptake, which is accomplished by upregulation of specific amino acid transporters. Since amino acid transporters differ in substrate selectivity, mode of transport, and driving forces, not all tumors rely on any single amino acid transporter for this purpose. Here we report on the differential upregulation of the amino acid transporter SLC38A5 in triple-negative breast cancer (TNBC). The upregulation is evident in primary TNBC tumors, conventional TNBC cell lines, patient-derived xenograft TNBC cell lines, and a mouse model of spontaneous mammary tumor representing TNBC. The upregulation is confirmed by functional assays. SLC38A5 is an amino acid-dependent Na+/H+ exchanger which transports Na+ and amino acids into cells coupled with H+ efflux. Since the traditional Na+/H+ exchanger is an established inducer of macropinocytosis, an endocytic process for cellular uptake of bulk fluid and its components, we examined the impact of SLC38A5 on macropinocytosis in TNBC cells. We found that the transport function of SLC38A5 is coupled to induction of macropinocytosis. Surprisingly, the transport function of SLC38A5 is inhibited by amilorides, the well-known inhibitors of Na+/H+ exchanger, possibly related to the amino acid-dependent Na+/H+ exchange function of SLC38A5. The Cancer Genome Atlas database corroborates SLC38A5 upregulation in TNBC. This represents the first report on the selective expression of SLC38A5 in TNBC and its role as an inducer of macropinocytosis, thus revealing a novel, hitherto unsuspected, function for an amino acid transporter that goes beyond amino acid delivery but is still relevant to cancer cell nutrition. Summary StatementSLC38A5 is an amino acid-coupled Na+/H+ exchanger that is upregulated in triple-negative breast cancer, and its function in cancer cells goes beyond amino acid delivery; it promotes macropinocytosis, a distinct form of endocytic process for cellular uptake of proteins and other nutrients present in extracellular fluid.