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

L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cell lines including C4-2 and PC-3, while poorly expressed in castration sensitive LNCaP cells. 5 μ M of JPH203 significantly blocked 14C leucine uptake in CRPC cells, while not affected in LNCaP cells. JPH203 inhibited cell migration at 30 μ M in CRPC cells, while not affected in LNCaP cells. Combination of JPH203 30 μ M and Enzalutamide 10 μ M additively blocked the cell proliferation in CRPC cells. RNA sequence identified CD24 as a novel downstream target of JPH203 in C4-2 cells. SiCD24 blocked cell migration in C4-2 cells via blocking phosphorylation of GSK3β and activating phosphorylation of β catenin. JPH203 25mg/kg significantly inhibited tumor growth in the C4-2 xenograft nude mouse model. Targeting LAT1 by JPH203 may represent a novel therapeutic option in CRPC.