Panoply™ Human EPRS Over-expressing Stable Cell Line

Glutamyl-prolyl-tRNA synthetase (EPRS/GluRS) is primarily found in a multi-synthetase complex, which may play a crucial role in cancer development and progression. However, the biological function, molecular mechanisms, and inhibitors of EPRS in gastric cancer have not yet been studied. Here, researchers found that EPRS expression was significantly elevated in gastric cancer tissues compared to adjacent normal tissues, and its high expression predicted poor prognosis in gastric cancer patients. Functionally, high expression of EPRS was positively correlated with gastric cancer development and progression both in vitro and in vivo. Mechanistically, EPRS directly binds to SCYL2, enhancing the activation of the WNT/GSK-3β/β-catenin signaling pathway and promoting the accumulation of β-catenin in the cell nucleus, thereby leading to gastric cancer cell proliferation and tumor growth. Furthermore, the researchers found that flavonol (XA) and 4-hydroxydihydrochalcone (4-HD) can directly bind to EPRS and block the WNT/GSK-3β/β-catenin signaling pathway. More importantly, XA and 4-HD inhibited the growth of patient-derived xenograft tumors and suppressed the development of Helicobacter pylori-induced atrophic gastritis and gastric tumors in combination with alcohol. These findings reveal a promising strategy for the prevention and treatment of gastric cancer by targeting the EPRS-mediated WNT/GSK-3β/β-catenin signaling pathway.

According to reports, SCYL2 can selectively induce the accumulation of Frizzled 5 (Frizzled proteins are seven-pass transmembrane receptor family proteins for WNT ligands) in the cytoplasm and participate in the WNT signaling pathway. Based on this result, researchers hypothesized that EPRS interacts with SCYL2 and participates in WNT signal transduction. They used cell lysates from EPRS knockdown or EPRS overexpression cells to detect WNT signaling pathway-related biomarkers: phosphorylated GSK-3β (Ser9), β-catenin, and c-MYC by Western blotting (WB). The results showed that after EPRS knockdown, phosphorylated GSK-3β (Ser9) significantly increased, while β-catenin and c-MYC significantly decreased (Figure 1a). EPRS overexpression cells showed the opposite trend (Figure 1b). Immunofluorescence (IF) detection showed that the accumulation of β-catenin in the nucleus was altered in EPRS-overexpressing 293T and KATO III cells or in EPRS-knockdown HGC27 and AGS cells (Figure 1c, d). These results were confirmed in vivo by immunohistochemical (IHC) staining of EPRS-knockdown CDX and PDX tumor tissues. These data indicate that EPRS enhances the activation of the WNT/GSK-3β/β-catenin signaling pathway, thereby promoting cancer cell proliferation and tumor growth.

Figure 1. EPRS promotes gastric cancer progression by enhancing activation of WNT/GSK-3β/β-catenin signaling pathway. (Liu H, et al., 2021)