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

Maihulan Maimaiti,Yoshikatsu Kanai,Keisuke Ando,Natasha Kyprianou,Yuzuru Ikehara,Atsushi Kaneda,Nobuyoshi Takeuchi,Naohiko Anzai,Kazuyoshi Nakamura,Tomohiko Ichikawa,Tomomi Furihata,Shinichi Sakamoto,Tomokazu Sazuka,Junryo Rii,Kosuke Higuchi,Masahiro Sugiura,Yusuke Imamura,Yasutaka Yamada,Minhui Xu

doi:10.1038/s41598-020-58136-x

Maihulan Maimaiti, Yoshikatsu Kanai + Show 17 more

Open Access

https://doi.org/10.1038/s41598-020-58136-x

Copy DOI

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.

Highlights

L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mammalian Target of Rapamycin (mTOR) signaling pathway
Among bladder cancer cell lines, the highest LAT1 protein expression was observed in 5637 cells, followed by T24 cells and EJ-1 cells (Fig. 1B)
In order to study the association between LAT1 and insulin-like growth factor-binding protein-5 (IGFBP-5) expression, we studied the effect of siLAT1 on IGFBP-5 expression and the effect of siIGFBP-5 on LAT1 expression

Summary

Introduction

L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment. The pathological type of BC is mainly urothelial cancer ( > 90%) and approximately 70% of patients had non-muscle-invasive BC at diagnosis[2]. JPH203 inhibits the function of the LAT1 in many types of cancer cells, which functions through the mTOR signaling pathway to block their migration/invasion activities and induce apoptosis[13,21]. JPH203 shows significant growth inhibition effects against xenografted human colon or biliary tract cancer cells[22,23], and its efficacy has been reported in a clinical trial of several cancers[24,25]. We examined the anti-tumour potential of JPH203, a specific inhibitor of LAT1, in BC cells

Methods

Results

Conclusion