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Title: Vitamin D analog TX 527 down-regulates the NFκB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus
Authors: González-Pardo, Veronica # ×
Verstuyf, Annemieke #
Boland, Ricardo #
Russo de Boland, Ana #
Issue Date: Aug-2013
Publisher: Scientific & Medical Division, Macmillan Press
Series Title: British journal of pharmacology vol:169 issue:7 pages:1635-45
Article number: 10.1111/bph.12219
Abstract: BACKGROUND AND PURPOSE: The Kaposi Sarcoma-associated herpesvirus G protein-coupled receptor (vGPCR) is a key molecule in the pathogenesis of Kaposi Sarcoma, where it increases Nuclear Factor kappa B (NFκB) gene expression and activates the NFκB pathway. We investigated whether the less calcemic vitamin D analog TX 527 inhibited the proliferation of endothelial cells transformed by vGPCR by modulation of the NFκB pathway. EXPERIMENTAL APPROACH: Endothelial cells transformed by vGPCR (SVEC-vGPCR) were treated with TX 527. Proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) and cell cycle by flow cytometry. mRNA and protein levels were measured by qRT-PCR and immunoblot analysis, respectively. KEY RESULTS: TX 527, similarly to bortezomib (0. 5 nM), a proteasome inhibitor that inhibits the activation of NFκB, reduced proliferation and induced G0/G1 cell cycle arrest in SVEC-vGPCR. TX 527 like 1α,25(OH)2 D3 ,biological active form of vitamin D, decreased the activity of NFκB comparable with the effect of bortezomib. Time-response studies showed that TX 527 significantly decreased NFκB and increased IκBα mRNA and protein levels. The increase of IκBα was accompanied by a reduction in p65/NFκB translocation to the nucleus. These responses were abolished when vitamin D receptor (VDR) expression was suppressed by stable transfection of shRNA against VDR. In parallel with NFκB inhibition, there was a down-regulation of inflammatory genes such as IL-6, CCL2/MCP and CCL20/MIP3α. CONCLUSIONS AND IMPLICATIONS: These results suggest that the antiproliferative effects of the vitamin D analog TX 527 in SVEC-vGPCR occur by modulation of the NFκB pathway and are VDR- dependent.
URI: 
ISSN: 0007-1188
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
× corresponding author
# (joint) last author

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