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

Autor: Alessia Aillon, Elisabetta Aldieri, Loredana Bergandi, Francesca Silvagno, Marta Viano, Chiara Ricca
Rok vydání: 2019
Předmět:
TGF-β
0301 basic medicine
Epithelial-Mesenchymal Transition
Endocrinology
Diabetes and Metabolism
Clinical Biochemistry
Motility
25(OH)2D3
Biochemistry
Calcitriol receptor
Cell Line
03 medical and health sciences
0302 clinical medicine
Endocrinology
Calcitriol
Transforming Growth Factor beta
medicine
Vitamin D and neurology
Humans
Gene silencing
Epithelial-mesenchymal EMT transition
Epithelial–mesenchymal transition
Molecular Biology
VDR
Membrane Potential
Mitochondrial
chemistry.chemical_classification
Reactive oxygen species
Chemistry
Vitamins
Cell Biology
1
25(OH)2D3
Mitochondrial respiratory activity
Molecular Medicine
Cell biology
Diabetes and Metabolism
030104 developmental biology
Mechanism of action
030220 oncology & carcinogenesis
Receptors
Calcitriol
medicine.symptom
Reactive Oxygen Species
Transforming growth factor
Zdroj: The Journal of Steroid Biochemistry and Molecular Biology. 187:97-105
ISSN: 0960-0760
DOI: 10.1016/j.jsbmb.2018.11.006
Popis: 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)2D3, 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.
Databáze: OpenAIRE
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