Targeting EPRS is an Effective Therapeutic Strategy for Gastric Cancer

Glutamyl-prolyl-tRNA synthetase (EPRS) is part of a multi-synthetase complex that catalyzes the attachment of the cognate amino acid to the corresponding tRNA; however, its role in cancer remains largely unknown. This study was conducted to identify the function, molecular mechanism and potential inhibitors of EPRS in gastric cancer. We believe that our study makes a significant contribution to the literature because we found that EPRS plays a functional role as an oncogene in gastric cancer. We also showed that EPRS accelerates tumor growth by interacting with SCYL2 to enhance kinase activity of GSK-3β and activate the WNT/GSK-3β/β-catenin signaling pathway. Xanthoangelol and 4-hydroxyderricin were identified as effective EPRS inhibitors that restrain gastric cancer patient-derived xenograft tumor growth and Helicobacter pylori combined with alcohol-induced gastric tumorigenesis. Our findings indicate that targeting the EPRS-mediated WNT/GSK-3β/β-catenin signaling pathway is a promising strategy for gastric cancer prevention and therapy. Additionally, xanthoangelol and 4-hydroxyderricin act as effective EPRS inhibitors and chemoprevention reagents, which may be clinically useful for gastric cancer prevention and therapy.