Cited 16 times in
Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer
DC Field | Value | Language |
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dc.contributor.author | 김은영 | - |
dc.contributor.author | 이정모 | - |
dc.contributor.author | 이진구 | - |
dc.contributor.author | 장윤수 | - |
dc.date.accessioned | 2019-07-11T03:14:21Z | - |
dc.date.available | 2019-07-11T03:14:21Z | - |
dc.date.issued | 2019 | - |
dc.identifier.issn | 1758-8340 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/169886 | - |
dc.description.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. | - |
dc.description.statementOfResponsibility | open | - |
dc.language | English | - |
dc.publisher | Sage | - |
dc.relation.isPartOf | THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.rights | https://creativecommons.org/licenses/by-nc-nd/2.0/kr/ | - |
dc.title | Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer | - |
dc.type | Article | - |
dc.contributor.college | College of Medicine (의과대학) | - |
dc.contributor.department | Dept. of Internal Medicine (내과학교실) | - |
dc.contributor.googleauthor | Eun Young Kim | - |
dc.contributor.googleauthor | Jin Gu Lee | - |
dc.contributor.googleauthor | Jung Mo Lee | - |
dc.contributor.googleauthor | Arum Kim | - |
dc.contributor.googleauthor | Hee Chan Yoo | - |
dc.contributor.googleauthor | Kibum Kim | - |
dc.contributor.googleauthor | Minji Lee | - |
dc.contributor.googleauthor | Chulho Lee | - |
dc.contributor.googleauthor | Gyoonhee Han | - |
dc.contributor.googleauthor | Jung Min Han | - |
dc.contributor.googleauthor | Yoon Soo Chang | - |
dc.identifier.doi | 10.1177/1758835919846798 | - |
dc.contributor.localId | A00811 | - |
dc.contributor.localId | A05384 | - |
dc.contributor.localId | A03225 | - |
dc.contributor.localId | A03456 | - |
dc.relation.journalcode | J02720 | - |
dc.identifier.eissn | 1758-8359 | - |
dc.identifier.pmid | 31205503 | - |
dc.subject.keyword | BC-LI-0186 | - |
dc.subject.keyword | aminoacyl-tRNA synthetase (ARS) | - |
dc.subject.keyword | leucyl-tRNA synthetase (LRS) | - |
dc.subject.keyword | mTORC1 | - |
dc.subject.keyword | non-small cell lung cancer (NSCLC) | - |
dc.contributor.alternativeName | Kim, Eun Young | - |
dc.contributor.affiliatedAuthor | 김은영 | - |
dc.contributor.affiliatedAuthor | 이정모 | - |
dc.contributor.affiliatedAuthor | 이진구 | - |
dc.contributor.affiliatedAuthor | 장윤수 | - |
dc.citation.volume | 11 | - |
dc.citation.startPage | 1758835919846798 | - |
dc.identifier.bibliographicCitation | THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, Vol.11 : 1758835919846798, 2019 | - |
dc.identifier.rimsid | 62011 | - |
dc.type.rims | ART | - |
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