Metabolism-Targeted Therapy Decreases Proliferation and Migration in CRC-Derived Cells by Modulating Wnt/β-Catenin Signaling Pathway

Abstract

: Background: Colorectal cancer (CRC) is the second most frequent cancer in women and the third most frequent in men. Current therapeutic approaches, including surgery, chemotherapy, and targeted therapy, often exhibit limited specificity and are associated with substantial adverse effects, compromising patient outcomes. Consequently, the medical community constantly pursues more efficient and precisely targeted therapeutic strategies. The aim of the study is to describe the effects of the TT on the Wnt/ β -catenin signaling pathway and its role in cell proliferation and migration in an azoxymethane/dextran sulfate sodium (AOM/DSS) mice model and colorectal cancer-derived cell lines. Methods: We treated AOM/DSS mice and HCT116 and SW620 cell lines with the TT, and measured Wnt target genes by quantitative polymerase chain reaction (qPCR) and western blot. β -catenin distribution, activation, transcriptional activity, cell proliferation, and migration were analyzed in HCT116 and SW620 cells. Results: We found that TT significantly decreased the number and size of tumors in AOM/DSS-treated animals. In colorectal cancer cell lines, the TT reduced the expression of AP-1 transcription factor subunit (c-Jun), cellular myelocytomatosis (c-Myc), snail family transcriptional repressor 1 (SNAIL), and vascular endothelial growth factor (VEGF) mRNAs and decreased the activation levels of β -catenin. The most relevant effect of the TT was the cellular delocalization of β -catenin from the nucleus. In addition, it significantly reduced cell proliferation and migration at 24 h in both cell lines. Conclusions: We established that TT decreases proliferation and migration by inducing an impaired localization of β -catenin and deregulation of the transcriptionally active state of this signaling pathway in colorectal cancer-derived cell lines and in a chemically induced mouse model.