Vitamin D analogue TX 527 down-regulates the NF-κB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus.

Abstract

BACKGROUND AND PURPOSE:

The Kaposi sarcoma (KS)-associated herpesvirus GPCR (vGPCR) is a key molecule in the pathogenesis of KS, where it increases NF-κB gene expression and activates the NF-κB pathway. We investigated whether the less calcemic vitamin D analogue TX 527 inhibited the proliferation of endothelial cells transformed by vGPCR by modulation of the NF-κB 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 real-time quantitative reverse transcriptase-PCR (qRT-PCR) and immunoblot analysis respectively.

KEY RESULTS:

TX 527, similar to bortezomib (0.5 nM), a proteasome inhibitor that inhibits the activation of NF-κB, 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 NF-κB comparable with the effect of bortezomib. Time-response studies showed that TX 527 significantly decreased NF-κB and increased IκBα mRNA and protein levels. The increase of IκBα was accompanied by a reduction in p65/NF-κB 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 NF-κB 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 anti-proliferative effects of the vitamin D analogue TX 527 in SVEC-vGPCR occur by modulation of the NF-κB pathway and are VDR dependent.

• Authors: V González-Pardo, A Verstuyf, R Boland, A Russo de Boland
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 169 Issue 7 Pg. 1635-45 (Aug 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23647513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• Alkynes
• Antineoplastic Agents
• Boronic Acids
• I-kappa B Proteins
• NF-kappa B
• Pyrazines
• inecalcitol
• Vitamin D
• Cholecalciferol
• Bortezomib

Topics

• Alkynes (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Boronic Acids (pharmacology)
• Bortezomib
• Cell Cycle (drug effects)
• Cell Line, Transformed
• Cell Proliferation (drug effects)
• Cholecalciferol (pharmacology)
• Endothelial Cells (metabolism, virology)
• Gene Expression Regulation
• Herpesvirus 8, Human (physiology)
• I-kappa B Proteins (genetics, metabolism)
• Mice
• NF-kappa B (genetics, metabolism)
• Pyrazines (pharmacology)
• Sarcoma, Kaposi (drug therapy)
• Signal Transduction (drug effects)
• Vitamin D (analogs & derivatives)