Therapeutic Effects of the Novel Leucyl-tRNA Synthetase Inhibitor BC-LI-0186 in Non-small Cell Lung Cancer

Overview

Journal Ther Adv Med Oncol

Specialty Oncology

Date 2019 Jun 18

PMID 31205503

Citations 11

Authors

Eun Young Kim

Jin Gu Lee

Jung Mo Lee

Arum Kim

Hee Chan Yoo

Kibum Kim

Minji Lee

Chulho Lee

Gyoonhee Han

Jung Min Han

Yoon Soo Chang

Affiliations

Soon will be listed here.

Abstract

Objective: Leucyl-tRNA synthetase (LRS) is an aminoacyl-tRNA synthetase catalyzing ligation of leucine to its cognate tRNA and is involved in the activation of mTORC1 by sensing cytoplasmic leucine. In this study, the usefulness of LRS as a therapeutic target of non-small cell lung cancer (NSCLC) and the anticancer effect of the LRS inhibitor, BC-LI-0186, was evaluated.

Methods: LRS expression and the antitumor effect of BC-LI-0186 were evaluated by immunohistochemical staining, immunoblotting, and live cell imaging. The antitumor effect of BC-LI-0186 was evaluated using Lox-Stop-Lox (LSL) K-ras G12D mice.

Results: LRS was frequently overexpressed in NSCLC tissues, and its expression was positively correlated with mTORC1 activity. The guanosine-5'-triphosphate (GTP) binding status of RagB was related to the expression of LRS and the S6K phosphorylation. RNA against LRS inhibited leucine-mediated mTORC1 activation and cell growth. BC-LI-0186 selectively inhibited phosphorylation of S6K without affecting phosphorylation of AKT and leucine-mediated co-localization of Raptor and LAMP2 in the lysosome. BC-LI-0186 induced cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3 and increase of p62 expression, showing that it has the autophagy-inducing property. BC-LI-0186 has the cytotoxic effect at nanomolar concentration and its GI value was negatively correlated with the degree of LRS expression. BC-LI-0186 showed the antitumor effect, which was comparable with that of cisplatin, and mTORC1 inhibitory effect in a lung cancer model.

Conclusions: BC-LI-0186 inhibits the noncanonical mTORC1-activating function of LRS. These results provide a new therapeutic strategy for NSCLC and warrant future clinical development by targeting LRS.

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