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Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer

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 
Citation
 THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, Vol.11 : 1758835919846798, 2019 
Journal Title
 THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY 
ISSN
 1758-8340 
Issue Date
2019
Keywords
BC-LI-0186 ; aminoacyl-tRNA synthetase (ARS) ; leucyl-tRNA synthetase (LRS) ; mTORC1 ; non-small cell lung cancer (NSCLC)
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 in vivo 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. siRNA 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 GI50 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.
Files in This Item:
T201901437.pdf Download
DOI
10.1177/1758835919846798
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Eun Young(김은영) ORCID logo https://orcid.org/0000-0002-3281-5744
Lee, Jung Mo(이정모)
Lee, Jin Gu(이진구)
Chang, Yoon Soo(장윤수) ORCID logo https://orcid.org/0000-0003-3340-4223
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/169886
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