Tamarixetin Suppresses Colorectal Cancer Progression by Targeting DPP7-Mediated WNT3A/β-Catenin Signalling Pathway

Abstract

Colorectal cancer (CRC) patients have had limited benefits from conventional chemotherapy, highlighting the need for improved therapeutic strategies. Natural compounds have emerged as promising alternatives due to their potent anti-cancer properties and reduced side effects. Tamarixetin is an O-methylated flavonol derived from Azadirachta indica, but its potential and clinical utility to suppress CRC progression remain unknown. To figure out the underlying mechanism, the inhibitory effects of Tamarixetin on CRC were evaluated by in vitro assays; the validation of Tamarixetin-mediated tumour suppression was performed with CRC xenografts and patient-derived organoids. Our results demonstrated that Tamarixetin significantly reduced the proliferation of CRC cells (HT-29 and HCT-116) in a dose-dependent manner, with minimal effects on normal colonic epithelial cells (NCM460). Furthermore, Tamarixetin inhibited proliferation, migration, and invasion of CRC cells, leading to reduced xenograft tumour growth and sensitising CRC to Oxaliplatin. Mechanistically, The expression and protein levels of DPP7 in CRC cells were suppressed by Tamarixetin, which lead to the downregulation of WNT3A/β-catenin signalling pathway. This study highlights Tamarixetin as a promising natural compound for CRC treatment by interfering with DPP7-mediated WNT3A/β-catenin signalling pathway. These findings provide a novel therapeutic strategy to improve outcomes of CRC.