Vitamin D analogue TX 527 down-regulates the NF-κB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus.
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 o...
| Published in: | British Journal of Pharmacology Vol. 169; no. 7; pp. 1635 - 1646 |
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| Main Authors: | , , , |
| Format: | research Journal Article |
| Published: |
Wiley-Blackwell
Aug2013
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=104081567&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 104081567 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00071188 DZ6 jtl: British Journal of Pharmacology issn: 00071188 maglogo: Y pubinfo: dt: Aug2013 vid: 169 iid: 7 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 104081567 104081567 NLM23647513 2012188821 10.1111/bph.12219 NLM23647513 PMC3724118 104081567 ppf: 1635 ppct: 11 formats: tig: atl: Vitamin D analogue TX 527 down-regulates the NF-κB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus. aug: au: González-Pardo, V Verstuyf, A Boland, R Russo de Boland, A affil: Departamento de Biología, Bioquímica & Farmacia, Universidad Nacional del Sur - Consejo Nacional de Investigaciones Científicas & Técnicas (CONICET), Bahía Blanca, Argentina. sug: subj: Antineoplastic Agents Pharmacodynamics Cholecalciferol Pharmacodynamics Epithelial Cells Herpesviruses Physiology Hydrocarbons, Acyclic Pharmacodynamics Sarcoma, Kaposi's Drug Therapy Signal Transduction Drug Effects Vitamin D Animal Studies Boron Compounds Pharmacodynamics Cell Cycle Drug Effects Cell Physiology Drug Effects Cells Epithelial Cells Metabolism Genes Heterocyclic Compounds Pharmacodynamics Mice Proteins Proteins Metabolism ab: 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. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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