Shinpei Saito, Keisuke Ando, Shinichi Sakamoto, Minhui Xu, Yasutaka Yamada, Junryo Rii, Sanji Kanaoka, Jiaxing Wei, Xue Zhao, Sangjon Pae, Manato Kanesaka, Yusuke Goto, Tomokazu Sazuka, Yusuke Imamura, Yoshie Reien, Norie Hamaguchi-Suzuki, Shota Saito, Yuri Hirayama, Hirofumi Hashimoto, Yoshikatsu Kanai, Tomohiko Ichikawa, Naohiko Anzai
Cancer science 2024年4月24日
L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated 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) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/β-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.