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

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) an...

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Autores principales: Kim, Eun Young, Lee, Jin Gu, Lee, Jung Mo, Kim, Arum, Yoo, Hee Chan, Kim, Kibum, Lee, Minji, Lee, Chulho, Han, Gyoonhee, Han, Jung Min, Chang, Yoon Soo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535710/
https://www.ncbi.nlm.nih.gov/pubmed/31205503
http://dx.doi.org/10.1177/1758835919846798
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author Kim, Eun Young
Lee, Jin Gu
Lee, Jung Mo
Kim, Arum
Yoo, Hee Chan
Kim, Kibum
Lee, Minji
Lee, Chulho
Han, Gyoonhee
Han, Jung Min
Chang, Yoon Soo
author_facet Kim, Eun Young
Lee, Jin Gu
Lee, Jung Mo
Kim, Arum
Yoo, Hee Chan
Kim, Kibum
Lee, Minji
Lee, Chulho
Han, Gyoonhee
Han, Jung Min
Chang, Yoon Soo
author_sort Kim, Eun Young
collection PubMed
description 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 GI(50) 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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spelling pubmed-65357102019-06-14 Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer Kim, Eun Young Lee, Jin Gu Lee, Jung Mo Kim, Arum Yoo, Hee Chan Kim, Kibum Lee, Minji Lee, Chulho Han, Gyoonhee Han, Jung Min Chang, Yoon Soo Ther Adv Med Oncol Original Research 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 GI(50) 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. SAGE Publications 2019-05-19 /pmc/articles/PMC6535710/ /pubmed/31205503 http://dx.doi.org/10.1177/1758835919846798 Text en © The Author(s), 2019 http://www.creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Research
Kim, Eun Young
Lee, Jin Gu
Lee, Jung Mo
Kim, Arum
Yoo, Hee Chan
Kim, Kibum
Lee, Minji
Lee, Chulho
Han, Gyoonhee
Han, Jung Min
Chang, Yoon Soo
Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer
title Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer
title_full Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer
title_fullStr Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer
title_full_unstemmed Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer
title_short Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer
title_sort therapeutic effects of the novel leucyl-trna synthetase inhibitor bc-li-0186 in non-small cell lung cancer
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535710/
https://www.ncbi.nlm.nih.gov/pubmed/31205503
http://dx.doi.org/10.1177/1758835919846798
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