STM2457 impairs the proliferation of esophageal squamous cell carcinoma by activating DNA damage response through ATM-Chk2 axis.

Abstract

METTL3 has been proven to play an important role in the proliferation of Esophageal squamous cell carcinoma (ESCC). In this study, we focused on investigating the therapeutic role and molecular mechanism of STM2457 in ESCC, which is a novel small-molecule inhibitor of METTL3. The effect of STM2457 on ESCC was evaluated using ESCC cell lines by the cell viability measurement, cloning formation assay, scratching assay, transwell assay, and flow cytometry techniques. Furthermore, the molecular mechanism study was employed to evaluate by RT-qPCR, Western blotting, proteomics analysis, comet assay, etc. Additionally, the anticancer effect of STM2457 was carried out by nude mice tumor xenograft in vivo. This study showed STM2457 could significantly inhibit the proliferation and migration of Eca109 and KYSE150 cells, which promoted G0/G1 phase arrest and apoptosis in a dose-dependent manners in vitro. Moreover, proteomics analysis suggested the important role of ATM in action mechanism of STM2457. Further studies showed that STM2457 may activate DNA damage response and the expression of ATM, p-ATM, p-Chk2, and γ-H2AX protein in ATM-Chk2 pathway. Intriguingly, ATM inhibitor CGK-733 and knocking down ATM significantly reduced the expression of ATM in Eca109 and KYSE150 cells treated with STM2457. Importantly, STM2457 significantly upregulated the expression of ATM and γ-H2AX protein and inhibited the growth of ESCC in vivo. Finally, STM2457 combined with PTX could also significantly inhibit the proliferation and migration ability of Eca109 and KYSE150 cells by targeting the ATM-mediated DDR pathway. In tumor-bearing nude mice model, STM2457 combined with Paclitaxel can inhibit the growth of ESCC and increased the expression of ATM and γ-H2AX protein. These findings revealed ATM-Chk2 pathway is a promising therapeutic target for STM2457 to effectively inhibit the proliferation of ESCC.