Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer
Identifieur interne : 000327 ( Main/Exploration ); précédent : 000326; suivant : 000328Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer
Auteurs : 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 ChangSource :
- Therapeutic Advances in Medical Oncology [ 1758-8340 ] ; 2019.
Abstract
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.
LRS expression and the antitumor effect of BC-LI-0186 were evaluated by immunohistochemical staining, immunoblotting, and live cell imaging. The
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.
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.
Url:
DOI: 10.1177/1758835919846798
PubMed: 31205503
PubMed Central: 6535710
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer</title><author><name sortKey="Kim, Eun Young" sort="Kim, Eun Young" uniqKey="Kim E" first="Eun Young" last="Kim">Eun Young Kim</name></author><author><name sortKey="Lee, Jin Gu" sort="Lee, Jin Gu" uniqKey="Lee J" first="Jin Gu" last="Lee">Jin Gu Lee</name></author><author><name sortKey="Lee, Jung Mo" sort="Lee, Jung Mo" uniqKey="Lee J" first="Jung Mo" last="Lee">Jung Mo Lee</name></author><author><name sortKey="Kim, Arum" sort="Kim, Arum" uniqKey="Kim A" first="Arum" last="Kim">Arum Kim</name></author><author><name sortKey="Yoo, Hee Chan" sort="Yoo, Hee Chan" uniqKey="Yoo H" first="Hee Chan" last="Yoo">Hee Chan Yoo</name></author><author><name sortKey="Kim, Kibum" sort="Kim, Kibum" uniqKey="Kim K" first="Kibum" last="Kim">Kibum Kim</name></author><author><name sortKey="Lee, Minji" sort="Lee, Minji" uniqKey="Lee M" first="Minji" last="Lee">Minji Lee</name></author><author><name sortKey="Lee, Chulho" sort="Lee, Chulho" uniqKey="Lee C" first="Chulho" last="Lee">Chulho Lee</name></author><author><name sortKey="Han, Gyoonhee" sort="Han, Gyoonhee" uniqKey="Han G" first="Gyoonhee" last="Han">Gyoonhee Han</name></author><author><name sortKey="Han, Jung Min" sort="Han, Jung Min" uniqKey="Han J" first="Jung Min" last="Han">Jung Min Han</name></author><author><name sortKey="Chang, Yoon Soo" sort="Chang, Yoon Soo" uniqKey="Chang Y" first="Yoon Soo" last="Chang">Yoon Soo Chang</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31205503</idno><idno type="pmc">6535710</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535710</idno><idno type="RBID">PMC:6535710</idno><idno type="doi">10.1177/1758835919846798</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000811</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000811</idno><idno type="wicri:Area/Pmc/Curation">000811</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000811</idno><idno type="wicri:Area/Pmc/Checkpoint">000291</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000291</idno><idno type="wicri:Area/Ncbi/Merge">000707</idno><idno type="wicri:Area/Ncbi/Curation">000707</idno><idno type="wicri:Area/Ncbi/Checkpoint">000707</idno><idno type="wicri:doubleKey">1758-8340:2019:Kim E:therapeutic:effects:of</idno><idno type="wicri:Area/Main/Merge">000327</idno><idno type="wicri:Area/Main/Curation">000327</idno><idno type="wicri:Area/Main/Exploration">000327</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer</title><author><name sortKey="Kim, Eun Young" sort="Kim, Eun Young" uniqKey="Kim E" first="Eun Young" last="Kim">Eun Young Kim</name></author><author><name sortKey="Lee, Jin Gu" sort="Lee, Jin Gu" uniqKey="Lee J" first="Jin Gu" last="Lee">Jin Gu Lee</name></author><author><name sortKey="Lee, Jung Mo" sort="Lee, Jung Mo" uniqKey="Lee J" first="Jung Mo" last="Lee">Jung Mo Lee</name></author><author><name sortKey="Kim, Arum" sort="Kim, Arum" uniqKey="Kim A" first="Arum" last="Kim">Arum Kim</name></author><author><name sortKey="Yoo, Hee Chan" sort="Yoo, Hee Chan" uniqKey="Yoo H" first="Hee Chan" last="Yoo">Hee Chan Yoo</name></author><author><name sortKey="Kim, Kibum" sort="Kim, Kibum" uniqKey="Kim K" first="Kibum" last="Kim">Kibum Kim</name></author><author><name sortKey="Lee, Minji" sort="Lee, Minji" uniqKey="Lee M" first="Minji" last="Lee">Minji Lee</name></author><author><name sortKey="Lee, Chulho" sort="Lee, Chulho" uniqKey="Lee C" first="Chulho" last="Lee">Chulho Lee</name></author><author><name sortKey="Han, Gyoonhee" sort="Han, Gyoonhee" uniqKey="Han G" first="Gyoonhee" last="Han">Gyoonhee Han</name></author><author><name sortKey="Han, Jung Min" sort="Han, Jung Min" uniqKey="Han J" first="Jung Min" last="Han">Jung Min Han</name></author><author><name sortKey="Chang, Yoon Soo" sort="Chang, Yoon Soo" uniqKey="Chang Y" first="Yoon Soo" last="Chang">Yoon Soo Chang</name></author></analytic><series><title level="j">Therapeutic Advances in Medical Oncology</title><idno type="ISSN">1758-8340</idno><idno type="eISSN">1758-8359</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="section1-1758835919846798"><title>Objective:</title><p>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.</p></sec><sec id="section2-1758835919846798"><title>Methods:</title><p>LRS expression and the antitumor effect of BC-LI-0186 were evaluated by immunohistochemical staining, immunoblotting, and live cell imaging. The <italic>in vivo</italic> antitumor effect of BC-LI-0186 was evaluated using Lox-Stop-Lox (LSL) K-ras G12D mice.</p></sec><sec id="section3-1758835919846798"><title>Results:</title><p>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. <italic>si</italic>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<sub>50</sub> 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.</p></sec><sec id="section4-1758835919846798"><title>Conclusions:</title><p>BC-LI-0186 inhibits the noncanonical mTORC1-activating function of LRS. 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Blenis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aas, T" uniqKey="Aas T">T Aas</name></author><author><name sortKey="B Rresen, A L" uniqKey="B Rresen A">A-L Børresen</name></author><author><name sortKey="Geisler, S" uniqKey="Geisler S">S Geisler</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list></list><tree><noCountry><name sortKey="Chang, Yoon Soo" sort="Chang, Yoon Soo" uniqKey="Chang Y" first="Yoon Soo" last="Chang">Yoon Soo Chang</name><name sortKey="Han, Gyoonhee" sort="Han, Gyoonhee" uniqKey="Han G" first="Gyoonhee" last="Han">Gyoonhee Han</name><name sortKey="Han, Jung Min" sort="Han, Jung Min" uniqKey="Han J" first="Jung Min" last="Han">Jung Min Han</name><name sortKey="Kim, Arum" sort="Kim, Arum" uniqKey="Kim A" first="Arum" last="Kim">Arum Kim</name><name sortKey="Kim, Eun Young" sort="Kim, Eun Young" uniqKey="Kim E" first="Eun Young" last="Kim">Eun Young Kim</name><name sortKey="Kim, Kibum" sort="Kim, Kibum" uniqKey="Kim K" first="Kibum" last="Kim">Kibum Kim</name><name sortKey="Lee, Chulho" sort="Lee, Chulho" uniqKey="Lee C" first="Chulho" last="Lee">Chulho Lee</name><name sortKey="Lee, Jin Gu" sort="Lee, Jin Gu" uniqKey="Lee J" first="Jin Gu" last="Lee">Jin Gu Lee</name><name sortKey="Lee, Jung Mo" sort="Lee, Jung Mo" uniqKey="Lee J" first="Jung Mo" last="Lee">Jung Mo Lee</name><name sortKey="Lee, Minji" sort="Lee, Minji" uniqKey="Lee M" first="Minji" last="Lee">Minji Lee</name><name sortKey="Yoo, Hee Chan" sort="Yoo, Hee Chan" uniqKey="Yoo H" first="Hee Chan" last="Yoo">Hee Chan Yoo</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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