NFκB pathway is down-regulated by 1α,25(OH)2-vitamin D3 in endothelial cells transformed by Kaposi sarcoma-associated herpes virus G protein coupled receptor

We have previously demonstrated that 1 alpha,25 dihydroxy-vitamin D-3 (1 alpha,25(OH)(2)D-3) has antiproliferative effects on the growth of endothelial cells transformed by the viral G protein-coupled receptor associated to Kaposi sarcoma (vGPCR). In this work, we have investigated whether 1 alpha,25(OH)(2)D-3 exerts its growth inhibitory effects by inhibiting the Nuclear Factor kappa B (NF kappa B) pathway which is highly activated by vGPCR. Cell proliferation studies demonstrated that 1 alpha,25(OH)(2)D-3, similarly to bortezomib, a proteosome inhibitor that suppresses the activation of NF kappa B, reduced the proliferation of endothelial cells transformed by vGPCR (SVEC-vGPCR). The activity of NF kappa B in these cells decreased by 70% upon 1 alpha,25(OH)(2)D-3 treatment. Furthermore, time and dose response studies showed that the hormone significantly decreased NF kappa B and increased I kappa B alpha mRNA and protein levels in SVEC-vGPCR cells, whereas in SVEC only I kappa B alpha increased significantly. Moreover. NF kappa B translocation to the nucleus was inhibited and occurred by a mechanism independent of NF kappa B association with vitamin D-3 receptor (VDR). 1 alpha,25(OH)(2)D-3-induced increase in I kappa B alpha required de nova protein synthesis, and was independent of MAPK and PI3K/Akt pathways. Altogether, these results suggest that down-regulation of the NF kappa B pathway is part of the mechanism involved in the antiproliferative effects of 1 alpha,25(OH)(2)D-3 on endothelial cells transformed by vGPCR. (C) 2012 Elsevier Inc. All rights reserved.