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) 2 D 3 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 D 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) 2 D 3 abrogated the mitochondrial stimulation triggered by TGF-β. 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-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 D 3 in the prevention of cancer metastasis.

Calcitriol Inhibits Viability and Proliferation in Human Malignant Pleural Mesothelioma Cells

“…Possibly depending on both genomic (transcriptional) ( 35 ) or non-genomic (stabilization) ( 36 ) mechanisms, equally active after 24 h of treatment, we found that in MPM cell lines calcitriol increased VDR levels and promoted its nuclear translocation. Instead, basal VDR levels were modest in MeT-5A cells and remained unchanged after treatment with calcitriol, which would explain the lack of inhibitory activity in non-malignant cells, in line with previous findings ( 34 ). The induction of the catabolic enzyme 24-hydroxylase may justify the resistance of MeT-5A cells to vitamin D action, and possible differences among cell types, already described in other models ( 19 ), could be discovered also in mesothelial cells in future studies.…”

“…Calcitriol was previously found to increase VDR expression in different cancer cells, as well as in bronchial epithelial cells and peritoneal mesothelial cells, along with inhibition of epithelial to mesenchymal transition ( 5 , 8 , 34 ). However, the presence of VDR in MPM cell lines has yet to be examined.…”

Thermomagnetic resonance affects cancer growth and motility

“…The assay was carried out as previously described [10]. Cells were seeded in a 24-well plate and exposed to the specific frequency of ELF-EMF for 2 days in growth medium; they were then starved overnight again under exposure, with the aim of stopping proliferation.…”

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…Isoviolanthin, a flavonoid isolated from Dendrobium officinale Kimura et Migo, suppressed TGF‐β1‐induced EMT through inhibiting the TGF‐β1/Smad and phosphatidylinositol 3‐kinase (PI3K)/Akt/mTOR signaling pathways in hepatocellular carcinoma cells . In addition, vitamin D, a well‐known inhibitor of EMT, inhibited EMT by negatively regulating the TGF‐β1 signaling pathway in human bronchial epithelial cells, and MART‐10 (a vitamin D analogue) suppressed metastasis via downregulating EMT in pancreatic cancer cells …”