Metabolic reprogramming in cancer necessitates increased amino acid uptake, which is accomplished by up-regulation of specific amino acid transporters. However, not all tumors rely on any single amino acid transporter for this purpose. Here, we report on the differential up-regulation of the amino acid transporter SLC38A5 in triple-negative breast cancer (TNBC). The up-regulation is evident in TNBC tumors, conventional and patient-derived xenograft TNBC cell lines, and a mouse model of spontaneous TNBC mammary tumor. The up-regulation 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 cell-surface 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 the induction of macropinocytosis. Surprisingly, the transport function of SLC38A5 is inhibited by amilorides, the well-known inhibitors of Na+/H+ exchanger. Down-regulation of SLC38A5 in TNBC cells attenuates serine-induced macropinocytosis and reduces cell proliferation significantly as assessed by multiple methods, but does not induce cell death. The Cancer Genome Atlas database corroborates SLC38A5 up-regulation 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 and proliferation.

中文翻译：

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SLC38A5（一种氨基酸偶联的 Na+/H+ 交换剂）在三阴性乳腺癌中的表达和功能及其与巨胞饮作用的相关性

癌症中的代谢重编程需要增加氨基酸摄取，这是通过特定氨基酸转运蛋白的上调来实现的。然而，并非所有肿瘤都为此目的依赖任何单一的氨基酸转运蛋白。在这里，我们报告了氨基酸转运蛋白 SLC38A5 在三阴性乳腺癌 (TNBC) 中的差异上调。这种上调在 TNBC 肿瘤、传统和患者来源的异种移植 TNBC 细胞系以及自发性 TNBC 乳腺肿瘤的小鼠模型中很明显。通过功能测定证实了上调。SLC38A5 是一种氨基酸依赖性 Na+/H+ 交换器，可将 Na+ 和氨基酸转运到细胞中，并伴随 H+ 流出。由于细胞表面 Na+/H+ 交换剂是巨胞饮作用的既定诱导剂，这是一种细胞摄取大量液体及其成分的内吞过程，我们检查了 SLC38A5 对 TNBC 细胞中巨胞饮作用的影响。我们发现 SLC38A5 的转运功能与巨胞饮作用的诱导有关。令人惊讶的是，SLC38A5 的转运功能被众所周知的 Na+/H+ 交换剂抑制剂阿米洛利抑制。通过多种方法评估，TNBC 细胞中 SLC38A5 的下调减弱了丝氨酸诱导的巨胞饮作用并显着降低了细胞增殖，但不会诱导细胞死亡。癌症基因组图谱数据库证实了 TNBC 中 SLC38A5 的上调。这是关于 SLC38A5 在 TNBC 中选择性表达及其作为巨胞饮作用诱导剂作用的第一份报告，从而揭示了一种新的、迄今为止未曾预料的、