L-type amino acid transporter 1 (LAT1) is a major essential amino acid transporter in cancer. Leucine is one of the LAT1 substrates and acts as a signaling molecule to regulate cell growth and proliferation by stimulating mTORC1 pathway. Recently, several groups, include us, reported that inhibition of LAT1 suppresses the growth of cancer cells. The inhibition of LAT1 is a promising procedure for cancer therapeutics. Many researchers have been developing LAT1 inhibitors, but all of them inhibits LAT1 in a competitive manner. Due to abundant amounts of amino acids in living organisms, the competitive inhibition seems not to be the most practical way to control the function of the amino acid transporter in vivo. Thus, we have developed a series of non-competitive inhibitors of LAT1, called OKY compounds.
In this study, we found that a classical LAT1 competitive inhibitor, BCH, and one of the OKY compounds suppressed mTORC1 pathway in the same manner, and both compounds even made similar effects on comprehensive phosphoproteomes in vitro. These results indicate that the inhibition of LAT1 causes the same effect on cellular signaling in both competitive and non-competitive manners.