Vitamin D inhibits the epithelial-mesenchymal transition by a negative feedback regulation of TGF-β activity

Vitamin D and TGF-beta exert opposite effects on epithelial-mesenchymal EMT transition. Here we report a novel mechanism of action of TGF-beta that promotes the counteracting activity of vitamin D; in two models of human epithelial-mesenchymal EMT transition we demonstrated for the first time that TGF-beta strongly induced the expression of vitamin D receptor (VDR) and that 1,25(OH)(2)D-3 was able to contrast the TGF-beta-driven EMT transition by transcriptional modulation. In human bronchial epithelial cells the effects of TGF-beta on EMT transition markers (E-Cadherin expression and cell motility) were reversed by pre-treatment and co-treatment with 1,25(OH)(2)D-3, but not when the hormone was given later. Silencing experiments demonstrated that the inhibition of TGF-beta activity was VDR-dependent. 1,25(OH)(2)D-3 abrogated the mitochondrial stimulation triggered by TGF-beta. In fact we showed that 1,25(OH)(2)D-3 repressed the transcriptional induction of respiratory complex, limited the enhanced mitochondrial membrane potential and restrained the increased levels of mitochondrial ATP; 1,25(OH)(2)D-3 also decreased the production of reactive oxygen species promoted by TGF-beta. Overall, our study suggests that the overexpression and activity of VDR may be a regulatory response to TGF-beta signaling that could be exploited in clinical protocols, unraveling the therapeutic potentiality of 1,25(OH)(2)D-3 in the prevention of cancer metastasis.