Wnt and Vitamin D at the Crossroads in Solid Cancer

Abstract

Abnormal activation of the Wnt/β-catenin pathway is common in many types of solid cancers. Likewise, a large proportion of cancer patients have vitamin D deficiency. In line with these observations, Wnt/β-catenin signaling and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active vitamin D metabolite, usually have opposite effects on cancer cell proliferation and phenotype. In recent years, an increasing number of studies performed in a variety of cancer types have revealed a complex crosstalk between Wnt/β-catenin signaling and 1,25(OH)2D3. Here we review the mechanisms by which 1,25(OH)2D3 inhibits Wnt/β-catenin signaling and, conversely, how the activated Wnt/β-catenin pathway may abrogate vitamin D action. The available data suggest that interaction between Wnt/β-catenin signaling and the vitamin D system is at the crossroads in solid cancers and may have therapeutic applications.

Organoids and Colorectal Cancer

“…Organoid technology is also a unique system to elucidate the molecular and functional role of diverse agents in human disease in epithelial cells [ 115 , 116 ]. Based on the antitumor action of the active vitamin D metabolite 1α,25-dihydroxyvitamin D 3 (calcitriol) in CRC and other carcinomas and on its multilevel antagonism of the WNT/β-catenin pathway [ 117 ], our group has investigated the effects of this hormonal agent on human normal and tumor PDOs. RNA-seq assays revealed the profound and distinct regulatory effects of calcitriol on the transcription pattern in both types of PDOs [ 52 ].…”

Vitamin D Resistance as a Possible Cause of Autoimmune Diseases: A Hypothesis Confirmed by a Therapeutic High-Dose Vitamin D Protocol

“…Looking beyond the box of autoimmune diseases to the mounting evidence of Vitamin D as a player in tumor development ( 81 , 82 ), significant associations between SNPs of vitamin D system genes and common types of cancer (prostate, breast, colorectal and skin cancer) have been reported ( 83 , 84 ), suggesting a similar predisposing role of SNPs for cancer as for autoimmune diseases. In these cases, a partial blockade of the VDR by pathogens could be another pathway within the established infectious etiology of cancer ( 85 , 86 ).…”

Vitamin D and Hypoxia: Points of Interplay in Cancer

“…GSK-3β-mediated phosphorylation targets HIF-1α on multiple residues and decreases its protein levels in a process regulated by USP28/SENP1 [ 120 , 121 , 122 ]. It has been shown that calcitriol reduces the secretion of IL-1β, which inhibits GSK-3β [ 123 ]. Another HIF-1α destabilizing modification is mediated by direct HIF-1α phosphorylation at two sites (S576 and S657) by Polo Like Kinase 3 (PLK3) that targets HIF-1α for degradation in a VHL-independent manner [ 124 ].…”