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

DC Field Value Language
dc.contributor.author김은영-
dc.contributor.author이정모-
dc.contributor.author이진구-
dc.contributor.author장윤수-
dc.date.accessioned2019-07-11T03:14:21Z-
dc.date.available2019-07-11T03:14:21Z-
dc.date.issued2019-
dc.identifier.issn1758-8340-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/169886-
dc.description.abstractObjective: 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.statementOfResponsibilityopen-
dc.languageEnglish-
dc.publisherSage-
dc.relation.isPartOfTHERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.titleTherapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Internal Medicine (내과학교실)-
dc.contributor.googleauthorEun Young Kim-
dc.contributor.googleauthorJin Gu Lee-
dc.contributor.googleauthorJung Mo Lee-
dc.contributor.googleauthorArum Kim-
dc.contributor.googleauthorHee Chan Yoo-
dc.contributor.googleauthorKibum Kim-
dc.contributor.googleauthorMinji Lee-
dc.contributor.googleauthorChulho Lee-
dc.contributor.googleauthorGyoonhee Han-
dc.contributor.googleauthorJung Min Han-
dc.contributor.googleauthorYoon Soo Chang-
dc.identifier.doi10.1177/1758835919846798-
dc.contributor.localIdA00811-
dc.contributor.localIdA05384-
dc.contributor.localIdA03225-
dc.contributor.localIdA03456-
dc.relation.journalcodeJ02720-
dc.identifier.eissn1758-8359-
dc.identifier.pmid31205503-
dc.subject.keywordBC-LI-0186-
dc.subject.keywordaminoacyl-tRNA synthetase (ARS)-
dc.subject.keywordleucyl-tRNA synthetase (LRS)-
dc.subject.keywordmTORC1-
dc.subject.keywordnon-small cell lung cancer (NSCLC)-
dc.contributor.alternativeNameKim, Eun Young-
dc.contributor.affiliatedAuthor김은영-
dc.contributor.affiliatedAuthor이정모-
dc.contributor.affiliatedAuthor이진구-
dc.contributor.affiliatedAuthor장윤수-
dc.citation.volume11-
dc.citation.startPage1758835919846798-
dc.identifier.bibliographicCitationTHERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, Vol.11 : 1758835919846798, 2019-
dc.identifier.rimsid62011-
dc.type.rimsART-
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

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