The role of vitamin D in the Wnt/β-catenin signaling pathway

Abstract

Background. The Wnt/β-catenin signaling pathway is a complex system involved in immune homeostasis, tissue regeneration, and various physiological processes. Aberrant activation of the signaling pathway, driven by genetic and epigenetic changes, developes various cancers: colorectal carcinoma, gastric, esophageal, nasopharyngeal, breast. Objective of the study. To elucidate the biochemical mechanisms of action of vitamin D on the Wnt/β-catenin signaling pathway in order to develop effective methods of prevention and treatment in cancer. Materials and methods. A review of the literature from 2019-2024 was performed using 10 articles, including from the State University of Medicine and Pharmacy Nicolae Testemitanu Scientific Medical Library, Republic of Moldova, data from ScienceDirect, PubMed Central, Biomed Central, MDPI, Wiley Online Library, Febspress electronic libraries. Results. The canonical Wnt/β-catenin pathway regulates cell differentiation, proliferation, and survival. Physiologically, this pathway is initiated by the binding of Wnt ligands to frizzled (FZD) receptors, that associate with low-density lipoprotein receptor 5 (LRP5 ) and LRP6. Without Wnt receptor activation, β-catenin is phosphorylated by the destruction complex (DC), including glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), E3 ubiquitin ligase β-TrCP (SCFβ-TrCP), Axis inhibition protein (AXIN), and further degradation is carried out by proteasome. These processes prevent the accumulation of β-catenin in the nucleus and prevent further activation of the gene by the repressive complex containing theTCF/LEF family (T cell factor/lymphoid enhancer factor family). The Wnt/β-catenin pathway is activated when Wnt proteins bind to the FZD receptor, inhibiting DC and allowing β-catenin to accumulate in the cytoplasm, some of which translocates to the nucleus to activate TCF/LEF proteins. Abnormal expression of the signaling pathway causes excessive accumulation of β-catenin in tumor cells, which leads to tumor infiltration and metastasis progression. Calcitriol, 1,25(OH)₂D₃, inhibits Wnt signaling in cancer cells through vitamin D receptor (VDR), blocking β-catenin from binding TCF and activating target genes. Conclusions. Vitamin D administration significantly reduced Wnt and β-catenin expression, demonstrating its role in blocking β-catenin translocation. Currently, new strategies are being explored to develop effective drugs targeting this pathway for cancer treatment.