Role of Amino Acid Transporter SNAT1/SLC38A1 in Human Melanoma

Abstract

The tumor metabolism is an important driver of cancer cell survival and growth, as rapidly dividing tumor cells exhibit a high demand for energetic sources and must adapt to microenvironmental changes. Therefore, metabolic reprogramming of cancer cells and the associated deregulation of nutrient transporters are a hallmark of cancer cells. Amino acids are essential for cancer cells to synthesize the necessary amount of protein, DNA, and RNA. Although cancer cells can synthesize glutamine de novo, most cancer cells show an increased uptake of glutamine from the tumor microenvironment. Especially SNAT1/SLC38A1, a member of the sodium neutral amino acid transporter (SNAT) family, plays an essential role during major net import of glutamine. In this study, we revealed a significant upregulation of SNAT1 expression in human melanoma tissue in comparison to healthy epidermis and an increased SNAT1 expression level in human melanoma cell lines when compared to normal human melanocytes (NHEMs). We demonstrated that functional inhibition of SNAT1 with α-(methylamino) isobutyric acid (MeAIB), as well as siRNA-mediated downregulation reduces cancer cell growth, cellular migration, invasion, and leads to induction of senescence in melanoma cells. Consequently, these results demonstrate that the amino acid transporter SNAT1 is essential for cancer growth, and indicates a potential target for cancer chemotherapy.

Targeting glutamine metabolism as a therapeutic strategy for cancer

“…SLC38A1 (SNAT1) and SLC38A2 (SNAT2) are sodium-dependent neutral amino acid transporters that drive glutamine influx into cells 90 . SLC38A1 is overexpressed in melanoma, breast, gastric, osteosarcoma, and endometrial cancer cells, showing a close association with proliferation and migration [91][92][93] . SLC38A2 is highly expressed in prostate cancer, HCC, and TNBC cells, thereby contributing to tumorigenesis 94,95 .…”

HPV16 E6 and E7 Oncoproteins Stimulate the Glutamine Pathway Maintaining Cell Proliferation in a SNAT1-Dependent Fashion

“…In accordance with these data, ablation of SNAT1 was reported to decrease cell proliferation and migration in melanoma and gastric cancer cell models, evidencing that SNAT1 might play an important role in the maintenance of the malignant phenotype [ 61 , 62 ].…”

circTADA2A inhibited SLC38A1 expression and suppresses melanoma progression through the prevention of CNBP trans-activation

“…Importantly, the expression of SLC38A1 is significantly up-regulated in human melanoma tissue. Knockdown SLC38A1 expression reduce the proliferation rate of melanoma cells [ 29 ]. Consistent with this finding, we found that circTADA2A/CNBP represses the progression of melanoma by inhibiting the SLC38A1expression.…”