Triazole-quinoxaline attenuates epithelial-to-mesenchymal transition by suppressing the Wnt/β-catenin pathway in human colorectal cancer cells

Abstract

The Wnt/β-catenin signaling pathway regulates key cellular processes, including proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT). Dysregulation of this pathway has been implicated in various human cancers, including colorectal cancer (CRC), where it plays a critical role in promoting EMT and metastatic progression. In a recent study, triazole derivatives were shown to possess anti-EMT activity in cancer cells. Building on this finding, we synthesized a triazolyl-quinoxaline-based small molecule, SRN-18, and evaluated its impact on EMT in CRC cells. Specifically, we investigated the effect of SRN-18 on the mRNA and protein expression levels of CXCR4 and CXCR7, as well as its influence on the expression of MMP-2, MMP-9, and key EMT-associated proteins. As CXCL12 is a known ligand for both CXCR4 and CXCR7, we also examined the effects of CXCL12 stimulation on cell migration and invasion. Western blot analyses were conducted to determine whether SRN-18 modulates the expression of CXCR4/7, MMP-2/9, and EMT markers in the presence or absence of CXCL12 stimulation. Additionally, our findings revealed that the Wnt/β-catenin signaling pathway is involved in SRN-18-mediated EMT suppression. Since inhibition of the Wnt/β-catenin pathway has been shown to reduce the expression of CXCR4 and CXCR7, SRN-18-mediated suppression of this pathway led to the downregulation of CXCR4- and CXCR7-associated signaling proteins, including NF-κB and JNK. In summary, SRN-18 exerted its anti-EMT effects in colorectal cancer cells by targeting the Wnt/β-catenin signaling axis and its downstream signaling cascades.