Vitamin D inhibits the epithelial-mesenchymal transition by a negative feedback regulation of TGF-β activity. Issue 187 (March 2019)

• Record Type: Journal Article
• Authors: Ricca, Chiara; Aillon, Alessia; Viano, Marta; Bergandi, Loredana; Aldieri, Elisabetta; Silvagno, Francesca
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 187(2019)
• Page Start: 97
• Page End: 105
• Publication Date: 2019-03
• Subjects: EMT epithelial-mesenchymal EMT transition -- ROS reactive oxygen species -- COX2 cytochrome C oxidase subunit 2; VDR -- 1, 25(OH)2D3 -- TGF-β -- Epithelial-mesenchymal EMT transition -- Mitochondrial respiratory activity; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2018.11.006
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: In epithelial-mesenchymal transition TGFβ induces vitamin D receptor (VDR). 1, 25(OH)2 D3 contrasts the transition in a time-dependent modality. 1, 25(OH)2 D3 exerts a transcriptional and metabolic control over the transition. We demonstrated the metabolic switch promoted by TGFβ and reverted by 1, 25(OH)2 D3 . VDR activity may serve as a feedback mechanism to curb the toxic effects of TGF- β . 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)2 D3 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)2 D3, but not when the hormone was given later. Silencing experiments demonstrated that the inhibition of TGF-β activity was VDR-dependent. 1, 25(OH)2 D3 abrogated the mitochondrial stimulation triggered by TGF-β. In fact we showed that 1, 25(OH)2 D3 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 D3 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)2 D3 in the prevention of cancer metastasis.