Down-regulation of NF-kappaB signals is involved in loss of 1alpha,25-dihydroxyvitamin D3 responsiveness.
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Bao BY, Ting HJ, Hsu JW, Yasmin-Karim S, Messing E, Lee YF
Down-regulation of NF-kappaB signals is involved in loss of 1alpha,25-dihydroxyvitamin D3 responsiveness.
J Steroid Biochem Mol Biol. 2010 May;120(1):11-21. doi: 10.1016/j.jsbmb.2010.02.030. Epub 2010 Mar 4.
- PubMed ID
- 20206692 [ View in PubMed]
- Abstract
Vitamin D anti-tumor effect is often found reduced in the late stages of cancer. To uncover vitamin D resistance mechanism, we established a vitamin D-resistant human prostate cancer LNCaP cell line, LNCaP-R, by chronic exposure of cells to 1alpha,25-dihydroxyvitamin D(3) (1,25-VD). The vitamin D receptor (VDR)-mediated transcriptional activity was reduced in LNCaP-R, whereas VDR expression level and DNA-binding capacity were similar compared to parental cells (LNCaP-P). The expressions of the key factors involved in VDR transactivity, including CYP24A1 and VDR-associated proteins are all increased in LNCaP-R cells, and yet treatment with ketoconazole, P450 enzymes inhibitor, as well as trichostatin A (TSA), a histone deacetylase inhibitor, did not sensitize LNCaP-R cells response to vitamin D, suggesting that neither a local 1,25-VD availability, nor VDR-associated proteins are responsible for the vitamin D resistance. Interestingly, nuclear factor-kappaB (NF-kappaB) signaling, which is critical for 1,25-VD/VDR activity was found reduced in LNCaP-R cells, thereby treatment with NF-kappaB activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), can sensitize LNCaP-R vitamin D response. Together, we conclude that NF-kappaB signaling is critical for vitamin D sensitivity, and dysregulation of this pathway would result in vitamin D resistance and disease progression.