Inhibition of amino acid transporter LAT1 drastically suppresses the transport of large neutral amino acids and induces the downregulation of global translation in cancer cells

Abstract

Nutrient uptake is essential for maintaining the enhanced growth and proliferation of cancer cells. LAT1 (SLC7A5), which preferentially transports large neutral amino acids, is highly expressed in various cancers. LAT1 inhibitors are preclinically shown to suppress the cancer cell proliferation and tumor growth, and a representative compound JPH203 is under clinical evaluation. However, detailed pharmacological influence of LAT1 inhibition on the overall uptake of large neutral amino acids and the protein synthesis in cancer cells that are thought to be crucial for its anti-cancer effects have not been elucidated yet. Here, we showed that JPH203 dramatically inhibits the uptake of all the large neutral amino acids in multiple pancreatic cancer cell lines. We also found that JPH203 significantly inhibits the amino acid uptake even in cell culture media containing high concentrations of various amino acids. Analyses of the protein synthesis activity based on the binding state of mRNA with ribosomes (Polysome analysis) and the incorporation of puromycin into nascent polypeptides (SUnSET) revealed that JPH203 suppresses global translation. These results advance our understanding of pharmacological activities underlying the anti-cancer effects of LAT1 inhibitors, further supporting the adequacy of cancer treatments targeting LAT1.