Wnt and Vitamin D at the Crossroads in Solid Cancer

Simple Summary The Wnt/beta-catenin signaling pathway is aberrantly activated in most colorectal cancers and less frequently in a variety of other solid neoplasias. Many epidemiological and experimental studies and some clinical trials suggest an anticancer action of vitamin D, mainly against colorectal cancer. The aim of this review was to analyze the literature supporting the interference of Wnt/beta-catenin signaling by the active vitamin D metabolite 1 alpha,25-dihydroxyvitamin D-3. We discuss the molecular mechanisms of this antagonism in colorectal cancer and other cancer types. Additionally, we summarize the available data indicating a reciprocal inhibition of vitamin D action by the activated Wnt/beta-catenin pathway. Thus, a complex mutual antagonism between Wnt/beta-catenin signaling and the vitamin D system seems to be at the root of many solid cancers. Abnormal activation of the Wnt/beta-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/beta-catenin signaling and 1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), 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/beta-catenin signaling and 1,25(OH)(2)D-3. Here we review the mechanisms by which 1,25(OH)(2)D-3 inhibits Wnt/beta-catenin signaling and, conversely, how the activated Wnt/beta-catenin pathway may abrogate vitamin D action. The available data suggest that interaction between Wnt/beta-catenin signaling and the vitamin D system is at the crossroads in solid cancers and may have therapeutic applications.