title: Vitamin D analogue TX 527 down-regulates the NF-κB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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: Departamento de Biología, Bioquímica & Farmacia, Universidad Nacional del Sur - Consejo Nacional de Investigaciones Científicas & Técnicas (CONICET), Bahía Blanca, Argentina. vgpardo@criba.edu.ar
authors: V
authors: V
authors: González-Pardo
authors: A
authors: A
authors: Verstuyf
authors: R
authors: R
authors: Boland
authors: A
authors: A
authors: Russo de Boland
mesh_terms: D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology*; D005786:Gene Expression Regulation; D019288:Herpesvirus 8, Human / Q000502:physiology*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects*; D014807:Vitamin D / Q000031:analogs & derivatives*
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D001897:Boronic Acids; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011719:Pyrazines; C409043:inecalcitol; D014807:Vitamin D; D002762:Cholecalciferol; D000069286:Bortezomib
keywords: Kaposi sarcoma; NF-κB pathway; TX 527; VDR
references: J Cell Sci. 1997 Feb;110 ( Pt 3):369-78
references: 9057089
references: Mol Endocrinol. 2005 Nov;19(11):2685-95
references: 16002434
references: Anal Biochem. 1976 May 7;72:248-54
references: 942051
references: Int J Biochem Cell Biol. 2006;38(7):1181-90
references: 16483831
references: Nat Rev Cancer. 2007 Sep;7(9):684-700
references: 17721433
references: J Cell Biochem. 2003 Feb 1;88(2):223-6
references: 12520518
references: Oncogene. 2008 Dec;27 Suppl 2:S31-42
references: 19956178
references: Mol Immunol. 2010 May;47(9):1728-38
references: 20371119
references: J Immunol. 2011 Jan 1;186(1):132-42
references: 21131424
references: Annu Rev Immunol. 1996;14:649-83
references: 8717528
references: Annu Rev Pharmacol Toxicol. 2011;51:311-36
references: 20936945
references: Curr Med Chem. 2007;14(17):1893-910
references: 17627525
references: Am J Physiol Endocrinol Metab. 2006 Aug;291(2):E315-22
references: 16507601
references: J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):21-30
references: 16111885
references: J Steroid Biochem Mol Biol. 2009 Jan;113(1-2):134-8
references: 19138739
references: Endocrinology. 2010 Jan;151(1):23-31
references: 19915163
references: Mol Endocrinol. 2002 May;16(5):1029-39
references: 11981037
references: Biochem J. 2010 Sep 15;430(3):461-76
references: 20632995
references: Curr Opin Pharmacol. 2010 Aug;10(4):482-96
references: 20427238
references: Biochim Biophys Acta. 2010 Oct-Dec;1799(10-12):775-87
references: 20493977
references: Cancer Cell. 2004 Sep;6(3):203-8
references: 15380510
references: J Am Soc Nephrol. 2008 Sep;19(9):1741-52
references: 18525004
references: J Bone Miner Res. 1998 Mar;13(3):325-49
references: 9525333
references: Mol Biol Cell. 2001 Nov;12(11):3365-74
references: 11694573
references: Oncogene. 2008 Mar 20;27(13):1844-52
references: 17934524
references: Biochem Biophys Res Commun. 2001 Sep 14;287(1):292-300
references: 11549290
references: PLoS One. 2009 Jun 19;4(6):e5988
references: 19543524
references: Genes Dev. 2004 Sep 15;18(18):2195-224
references: 15371334
references: Endocrinol Metab Clin North Am. 2010 Jun;39(2):401-18, table of contents
references: 20511060
references: Mini Rev Med Chem. 2005 Aug;5(8):761-78
references: 16101412
references: Cancer Res. 2000 May 15;60(10):2673-9
references: 10825140
references: Cancer Res. 2001 Mar 15;61(6):2641-8
references: 11289142
references: Blood. 2004 Nov 1;104(9):2903-11
references: 15231571
references: Arch Biochem Biophys. 2011 Mar 15;507(2):241-7
references: 21176770
references: J Steroid Biochem Mol Biol. 2007 Jan;103(1):51-60
references: 17049230
references: Annu Rev Immunol. 2000;18:621-63
references: 10837071
references: Cancer Res. 2006 Jan 1;66(1):168-74
references: 16397229
references: Cancer Cell. 2003 Jan;3(1):23-36
references: 12559173
references: Cancer Res. 2000 Sep 1;60(17):4873-80
references: 10987301
references: Nat Rev Cancer. 2010 Oct;10(10):707-19
references: 20865011
references: Clin Exp Immunol. 2006 Jan;143(1):58-64
references: 16367934
references: Transplantation. 2000 May 15;69(9):1932-42
references: 10830234
references: Steroids. 2012 Sep;77(11):1025-32
references: 22683670