PMID- 31205503
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220408
IS  - 1758-8340 (Print)
IS  - 1758-8359 (Electronic)
IS  - 1758-8340 (Linking)
VI  - 11
DP  - 2019
TI  - Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in 
      non-small cell lung cancer.
PG  - 1758835919846798
LID - 10.1177/1758835919846798 [doi]
LID - 1758835919846798
AB  - 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.
FAU - Kim, Eun Young
AU  - Kim EY
AD  - Department of Internal Medicine, Yonsei University College of Medicine, Yonsei 
      University, Seoul, South Korea.
FAU - Lee, Jin Gu
AU  - Lee JG
AD  - Department of Thoracic and Cardiovascular Surgery, Yonsei University College of 
      Medicine, Yonsei University, Seoul, South Korea.
FAU - Lee, Jung Mo
AU  - Lee JM
AD  - Department of Internal Medicine, Yonsei University College of Medicine, Yonsei 
      University, Seoul, South Korea.
FAU - Kim, Arum
AU  - Kim A
AD  - Department of Internal Medicine, Yonsei University College of Medicine, Yonsei 
      University, Seoul, South Korea.
FAU - Yoo, Hee Chan
AU  - Yoo HC
AD  - College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei 
      University, Seoul, South Korea.
FAU - Kim, Kibum
AU  - Kim K
AD  - College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei 
      University, Seoul, South Korea.
FAU - Lee, Minji
AU  - Lee M
AD  - College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei 
      University, Seoul, South Korea.
FAU - Lee, Chulho
AU  - Lee C
AD  - Translational Research Center for Protein Function Control, Department of 
      Biotechnology, Yonsei University, Seoul, South Korea.
FAU - Han, Gyoonhee
AU  - Han G
AD  - Translational Research Center for Protein Function Control, Department of 
      Biotechnology, Yonsei University, Seoul, South Korea.
FAU - Han, Jung Min
AU  - Han JM
AD  - College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei 
      University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, South Korea.
FAU - Chang, Yoon Soo
AU  - Chang YS
AUID- ORCID: 0000-0003-3340-4223
AD  - Department of Internal Medicine, Yonsei University College of Medicine, Yonsei 
      University, 4th Floor, Research Center for Future Medicine, 20, Eonju-ro 63-gil, 
      Gangnam-gu, Seoul, 06229, South Korea.
LA  - eng
PT  - Journal Article
DEP - 20190519
PL  - England
TA  - Ther Adv Med Oncol
JT  - Therapeutic advances in medical oncology
JID - 101510808
PMC - PMC6535710
OTO - NOTNLM
OT  - BC-LI-0186
OT  - aminoacyl-tRNA synthetase (ARS)
OT  - leucyl-tRNA synthetase (LRS)
OT  - mTORC1
OT  - non-small cell lung cancer (NSCLC)
COIS- Conflict of interest statement: The authors declare that there are no conflicts 
      of interest.
EDAT- 2019/06/18 06:00
MHDA- 2019/06/18 06:01
PMCR- 2019/05/19
CRDT- 2019/06/18 06:00
PHST- 2018/10/13 00:00 [received]
PHST- 2019/04/04 00:00 [accepted]
PHST- 2019/06/18 06:00 [entrez]
PHST- 2019/06/18 06:00 [pubmed]
PHST- 2019/06/18 06:01 [medline]
PHST- 2019/05/19 00:00 [pmc-release]
AID - 10.1177_1758835919846798 [pii]
AID - 10.1177/1758835919846798 [doi]
PST - epublish
SO  - Ther Adv Med Oncol. 2019 May 19;11:1758835919846798. doi: 
      10.1177/1758835919846798. eCollection 2019.