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

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. si 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 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.

Interactions of Destruxin A with Silkworms’ Arginine tRNA Synthetase and Lamin-C Proteins

“…Aminoacyl tRNA synthetases play an important role in protein synthesis and are usually considered as medicine targets [19][20][21]; among them, ArgRS is involved in the formation of arginyl-tRNA Arg complex in peptide chain extension [22]. Sequence analysis indicates that BmArgRS contains a catalytic core domain of arginyl-tRNA synthetases in the region of 216-481.…”

tRNA Metabolism and Lung Cancer: Beyond Translation

“…As ARSs and AIMPs are closely related to the development of tumors, they may become potential targets for tumor treatment. LRS played an important role in activating the mTORC1 pathway and cell growth ( Kim et al, 2019 ). Interestingly, the new LRS inhibitor BC-LI-0186 inhibited the mTORC1 signaling pathway by interacting with the RagD site of LRS, leading to the cytotoxicity of NSCLC cells and anticancer effects in the K-ras mouse lung cancer model ( Kim et al, 2017b ; Kim et al, 2019 ).…”

“…LRS played an important role in activating the mTORC1 pathway and cell growth ( Kim et al, 2019 ). Interestingly, the new LRS inhibitor BC-LI-0186 inhibited the mTORC1 signaling pathway by interacting with the RagD site of LRS, leading to the cytotoxicity of NSCLC cells and anticancer effects in the K-ras mouse lung cancer model ( Kim et al, 2017b ; Kim et al, 2019 ). These results provide a new therapeutic strategy for NSCLC.…”

Roles of Aminoacyl-tRNA Synthetases in Cancer

“…Since ARSs are closely related to tumor development, they may serve as potential targets for cancer treatment ( Figure 4 ). LRS was often overexpressed in lung cancer tissues and performed an important function in the activation of mTORC1 and cell growth ( Kim et al, 2019 ). The novel LRS inhibitor BC-LI-0186 could inhibit mTORC1 signaling, resulting in cytotoxicity to NSCLC cells and anticancer effects in K-ras mouse lung cancer model ( Kim et al, 2019 ).…”

“…LRS was often overexpressed in lung cancer tissues and performed an important function in the activation of mTORC1 and cell growth ( Kim et al, 2019 ). The novel LRS inhibitor BC-LI-0186 could inhibit mTORC1 signaling, resulting in cytotoxicity to NSCLC cells and anticancer effects in K-ras mouse lung cancer model ( Kim et al, 2019 ). In this process, BC-LI-0186 bound to the RagD interacting site of LRS, thus suppressing the lysosomal localization and activity of mTORC1 ( Kim J.H.…”