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: 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.
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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)
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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
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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)
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