Mechanisms of the inhibition of cancer cell proliferation by LAT1 inhibitors revealed by the changes in the intracellular concentrations and function of individual amino acids

Abstract

Nanvuranlat (JPH203, KYT-0353), an inhibitor for L-type amino acid transporter 1 (LAT1; SLC7A5), suppresses the cancer cell proliferation and tumor growth by inhibiting the uptake of large neutral amino acids into cancer cells. Most previous studies have focused on the inhibition of leucine uptake to describe the pharmacological effects of nanvuranlat, mainly because leucine is an essential amino acid that functions as activating signaling molecules of cellular metabolism. In this study, to elucidate the anti-cancer effects of LAT1 inhibitors in more detail, we focused on changes in the intracellular concentrations of all the LAT1 substrates and their importance on cell proliferation. Surprisingly, high-performance liquid chromatography analysis revealed that only three large neutral amino acids were continuously decreased by the treatment with nanvuranlat. Similar changes were commonly observed in multiple cancer cell lines. Culturing the cells in media depleted with each or all of the three amino acids reduced the intracellular amount of corresponding amino acids, partially recapitulating the effects of nanvuranlat on cell proliferation, amino acid signaling, and cell cycle arrest. These findings contribute to understanding the molecular basis underlying the anti-cancer effects of LAT1 inhibitors.