Role of Amino Acid Transporter SNAT1/SLC38A1 in Human Melanoma.

Abstract

Simple SummaryMalignant melanoma originates from melanocytes. Due to its high metastatic potential and its increasing incidence, it is one of the most aggressive types of cancer. Cancer cells generally exhibit an elevated metabolism, consequently adapting their expression of transport proteins to meet the increased demand of nutrients, such as amino acids. The aim of this study was to analyze the expression and function of the amino acid transporter SNAT1 in human melanoma. In addition, we wanted to determine its role in development and progression of malignant melanoma. We revealed that SNAT1 is overexpressed in melanoma tissue samples, as well as primary and metastatic cell lines. Moreover, we were able to show that SNAT1 plays an important role in forcing proliferation, colony formation, migration and invasion, and inhibiting senescence of melanoma cells. Amino acid transporters like SNAT1 are therefore promising targets for the development of novel therapeutic strategies against melanoma.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.