THE VITAMIN D ANALOGUE TX 527 INHIBITS NFKB PATHWAY AND INDUCES CELL CYCLE ARREST IN ENDOTHELIAL CELLS TRANSFORMED BY KAPOSI SARCOMA-ASSOCIATED HERPES VIRUS G PROTEIN COUPLED RECEPTOR

VERONICA GONZALEZ PARDO; ANNEMIEKE VERSTUYF; RICARDO BOLAND; ANA RUSSO DE BOLAND

Houston

Congreso; 15 TH VITAMIN D WORKSHOP; 2012

The Kaposi Sarcoma-associated herpes virus G protein-coupled receptor (vGPCR) is a key molecule in the pathogenesis of Kaposi Sarcoma, where it increases Nuclear Factor k B (NFkB) gene expression and activates the NFkB pathway. In this study we investigated whether the vitamin D analogue TX 527 inhibited the proliferation of the endothelial cells transformed by vGPCR by modulation of the NFkB pathway. Assessment of cell proliferation (MTS assay) and cell cycle distribution (by flow cytometry) demonstrated that TX 527, similarly to bortezomib (0. 5 nM), a proteosome inhibitor that inhibits the activation of NFκB, reduced the proliferation and induced G0/G1 cell cycle arrest in endothelial cells transformed by vGPCR (SVEC-vGPCR). Time-response studies showed that TX 527 significantly decreased NFkB and increased IkBα mRNA and protein levels. The increase of IkBα was accompanied by a reduction in p65/NFkB translocation to the nucleus. These responses were reverted when vitamin D receptor (VDR) expression was blocked by stable transfection of shRNA against VDR. In parallel with NFκB inhibition, there was a down-regulation of inflammatory genes such as IL-6, MIP3α, and MCP. Altogether, these results suggested that the antiproliferative effects of the vitamin D analogue TX 527 in SVEC-vGPCR occurred by immune modulation of the NFkB pathway