A human leucyl-tRNA synthetase as an anticancer target

Abstract

Several aminoacyl-tRNA synthetases have been reported to be overexpressed for charging essential aminoacyl-tRNAs in many cancer types. In this study, we aimed to explore the potential role of leucyl-tRNA synthetase (LARS) as an anticancer target. MTT assay was performed to screen inhibitors to human LARS (hsLARS) from compounds AN2690 and its derivatives, compounds 1–6, in U2OS and SKOV3 cells. The compound with the strongest inhibitory ability was further investigated for its inhibitory effect in cancer cell lines and in an animal tumor model. Additionally, a LARS-rescue experiment was performed to explore the potential target in U2OS using Western blot and flow cytometry. Luciferase reporter assay was designed to analyze the effect of of hsLARS inhibitor on p21 activation. We identified an hsLARS inhibitor (compound 2) that suppressed the proliferation of U2OS and SKOV3 cells in vitro. A LARS-rescue experiment demonstrated that the proliferation inhibition was induced by targeting intracellular LARS. In addition, the hsLARS inhibition was shown to activate the p21 early transcription and promote cell apoptosis, as well as reduce implanted EMT6 tumor progression in mice. Our results suggest that LARS might serve as a potential anticancer target through the p21 signaling pathway and that the nutritional signaling pathway may provide a valuable anticancer strategy for further investigation.

Correlation of histopathologic characteristics to protein expression and function in malignant melanoma

“…Aminoacyl tRNA synthetases are believed to be involved in tumorigenesis presumably involving their additional domains which are not directly responsible to their biosynthetic activities [ 40 ]. Recently, one aminoacyl tRNA synthetase was used as a cancer drug target [ 41 ]. Other pathways and processes manifested by the proteins correlated to tumor percentage, include mitochondrial proteins (more than 80 among significantly correlated) and N-cadherin signaling (including catenins alpha-1, beta-1 and delta-1).…”

Discovering simple phenylboronic acid and benzoxaborole derivatives for experimental oncology – phase cycle-specific inducers of apoptosis in A2780 ovarian cancer cells

“…Studies by Gao et al indicated LeuRS as a potential target for 21 and some of its derivatives in human osteosarcoma (U2OS) and ovarian cancer (SKOV-3) cells. The apoptotic morphology associated with the ambiguous transcriptional activity of the p21 promotor and no significant impact on the cell cycle was reported [41].…”

Dickkopf 4 Alone and in Combination with Leucyl‐tRNA Synthetase as a Good Prognostic Biomarker for Human Colorectal Cancer

“…LARS expression was reported to be upregulated in several cancers including lung cancer [6,8]. Thus, many investigators have tried to develop novel anticancer agents targeting LARS [7][8][9][10][11][12][13]. However, the biological and clinical significance of LARS expression in CRC has not been reported yet.…”

“…LARS was reported to be closely related to the growth and migration of lung cancer cells by observing the reduced migration and colony formation from LARS1 siRNA knockdown in a lung cancer cell line [6]. LARS expression has no reported biological or clinical implications in CRC patients, even though a few compounds targeting LARS as potential anticancer agents have been developed and their action mechanisms are studied [7][8][9][10][11][12][13].…”