Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma.

Abstract

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.

• Authors: 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
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 1292 (Jan 28 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 31992742 (Publication Type: Journal Article)

Chemical References

• 2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid
• Benzoxazoles
• Large Neutral Amino Acid-Transporter 1
• Neoplasm Proteins
• SLC7A5 protein, human
• Tyrosine
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases

Topics

• Benzoxazoles (pharmacology)
• Cell Line, Tumor
• Disease-Free Survival
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Large Neutral Amino Acid-Transporter 1 (biosynthesis)
• MAP Kinase Signaling System
• Male
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis)
• Survival Rate
• TOR Serine-Threonine Kinases (metabolism)
• Tyrosine (analogs & derivatives, pharmacology)
• Urinary Bladder Neoplasms (drug therapy, metabolism, microbiology, pathology)