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 bladder cancer.
Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.
Scientific reports. 2020 Jan 28*** epublish ***
Maihulan Maimaiti, Shinichi Sakamoto, Yasutaka Yamada, Masahiro Sugiura, Junryo Rii, Nobuyoshi Takeuchi, Yusuke Imamura, Tomomi Furihata, Keisuke Ando, Kosuke Higuchi, Minhui Xu, Tomokazu Sazuka, Kazuyoshi Nakamura, Atsushi Kaneda, Yoshikatsu Kanai, Natasha Kyprianou, Yuzuru Ikehara, Naohiko Anzai, Tomohiko Ichikawa
Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan., Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan. ., Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan., Bio-system Pharmacology, Osaka University Graduate School of Medicine, Osaka, Japan., Department of Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan., Department of Urology, University of Kentucky College of Medicine, Lexington, KY, USA., Department of Tumor Pathology, Chiba University Graduate School of Medicine, Chiba, Japan.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/31992742