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

Abstract

Vitamin D and TGF-β exert opposite effects on epithelial-mesenchymal EMT transition. Here we report a novel mechanism of action of TGF-β 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-β strongly induced the expression of vitamin D receptor (VDR) and that 1,25(OH)₂D₃ was able to contrast the TGF-β-driven EMT transition by transcriptional modulation. In human bronchial epithelial cells the effects of TGF-β on EMT transition markers (E-Cadherin expression and cell motility) were reversed by pre-treatment and co-treatment with 1,25(OH)₂D_3, but not when the hormone was given later. Silencing experiments demonstrated that the inhibition of TGF-β activity was VDR-dependent. 1,25(OH)₂D₃ abrogated the mitochondrial stimulation triggered by TGF-β. In fact we showed that 1,25(OH)₂D₃ repressed the transcriptional induction of respiratory complex, limited the enhanced mitochondrial membrane potential and restrained the increased levels of mitochondrial ATP; 1,25(OH)₂D₃ also decreased the production of reactive oxygen species promoted by TGF-β. Overall, our study suggests that the overexpression and activity of VDR may be a regulatory response to TGF-β signaling that could be exploited in clinical protocols, unraveling the therapeutic potentiality of 1,25(OH)₂D₃ in the prevention of cancer metastasis.

Keywords: 1,25(OH)(2)D(3); Epithelial-mesenchymal EMT transition; Mitochondrial respiratory activity; TGF-β; VDR.