NFκB pathway is down-regulated by 1α,25(OH)(2)-vitamin D(3) in endothelial cells transformed by Kaposi sarcoma-associated herpes virus G protein coupled receptor.
We have previously demonstrated that 1α,25 dihydroxy-vitamin D(3) (1α,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 1α,25(OH)(2)D(3) exerts its growth inhibitory effects by inhibiting the Nuclear Factor κ B (NFκB) pathway which is highly activated by vGPCR. Cell proliferation studies demonstrated that 1α,25(OH)(2)D(3), similarly to bortezomib, a proteosome inhibitor that suppresses the activation of NFκB, reduced the proliferation of endothelial cells transformed by vGPCR (SVEC-vGPCR). The activity of NFκB in these cells decreased by 70% upon 1α,25(OH)(2)D(3) treatment. Furthermore, time and dose response studies showed that the hormone significantly decreased NFκB and increased IκBα mRNA and protein levels in SVEC-vGPCR cells, whereas in SVEC only IκBα increased significantly. Moreover, NFκB translocation to the nucleus was inhibited and occurred by a mechanism independent of NFκB association with vitamin D(3) receptor (VDR). 1α,25(OH)(2)D(3)-induced increase in IκBα required de novo protein synthesis, and was independent of MAPK and PI3K/Akt pathways. Altogether, these results suggest that down-regulation of the NFκB pathway is part of the mechanism involved in the antiproliferative effects of 1α,25(OH)(2)D(3) on endothelial cells transformed by vGPCR.
Departamento de Biología, Bioquímica & Farmacia, Universidad Nacional del Sur, San Juan 670, 8000 Bahía Blanca, Argentina. vgpardo@criba.edu.ar
Verónica
V
Gonzalez-Pardo
Noelia
N
D'Elia
Annemieke
A
Verstuyf
Ricardo
R
Boland
Ana
A
Russo de Boland
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002117:Calcitriol / Q000494:pharmacology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D011719:Pyrazines / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics*; D011991:Receptors, Virus / Q000235:genetics*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D001897:Boronic Acids; C115448:G protein-coupled receptor, Human herpesvirus 8; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011719:Pyrazines; D018167:Receptors, Calcitriol; D019707:Receptors, Chemokine; D011991:Receptors, Virus; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D002117:Calcitriol