L-type amino acid transporter 1 inhibitor JPH203 as a new therapeutic target for castration resistant prostate cancer treatment

<p>LAT1 (SLC7A5) is a type of amino acid transporter that transports many essential amino acids, including Leucine, into cells. High expression of LAT1 is associated with poor prognosis in a variety of carcinomas, and a selective inhibitor of LAT1 (JPH203) has been reported to inhibit cancer cell growth. Recently, we reported that LAT1 expression is upregulated in the cell line C4-2, a model of castration-resistant prostate cancer (CRPC). We hypothesized that JPH203 could be a novel therapeutic agent for CRPC. We examined the effects of JPH203 in C4-2 and PC-3 cell lines as a model of CRPC and LNCaP cell line as hormone-sensitive prostate cancer (HSPC). We performed [14C] Leucine uptake assay for functional analysis and WST-8 assay for cytotoxicity test. In addition, Migration/Invasion assay was performed using Corning™ Falcon™ Cell Culture Inserts to evaluate cell migration and invasion ability. To elucidate the molecular mechanism of the inhibitory effect on proliferation, the presence or absence of mTOR pathway inhibition was verified using Western blotting. We also investigated the tumor suppressive effect of JPH203 in mice injected subcutaneously with C4-2 cells. As a result, Leucine uptake was predominantly decreased by JPH203 in C4-2 and PC-3 cells, and the inhibitory effect on cell proliferation was also confirmed. In C4-2 cells, JPH203 inhibited the mTOR pathway. JPH203 suppressed tumor growth in vivo. These results suggest that JPH203 may have an antitumor effect on CRPC and may be a novel therapeutic agent.</p>