Mechanism of 1alfa,25(OH)2D3 induced growth inhibition of transformed endothelial cells

VERONICA GONZALEZ PARDO; RICARDO BOLAND; ANA RUSSO DE BOLAND

Washington DC, USA

Congreso; Experimental Biology 2011; 2011

We have previously demonstrated that 1,25(OH)2-Vitamin D3 (1,25(OH)2D3) has antiproliferative effects on the growth of endothelial cells transformed by the viral G protein-coupled receptor associated to Kaposi sarcoma (KSHV-GPCR). In this work, we have investigated whether 1,25(OH)2D3 exerts its growth inhibitory effects by interfering with the NFkB pathway which is activated by vGPCR and serum in endothelial cells (SVEC). Time (4-48 h) and dose (0.1-100 nM) response studies showed that the hormone decreases NFkB and increases IkBα protein levels in SVEC and SVEC-vGPCR cells, the highest response taking place at 16 h and 10 nM 1,25(OH)2D3. Moreover, inhibition of NFkB translocation to the nucleus was observed and occurred by a mechanism independent of NFkB association with vitamin D3 receptor (VDR). IkBα protein synthesis was decreased in presence of cycloheximide, demonstrating that de novo IkBα synthesis is induced by 1,25(OH)2D3. The role of Akt and MAPK pathways on hormone modulation of NFkB was investigated. The results indicated that inhibition of Akt by LY 249002 mimics 1,25(OH)2D3 induction of IkBα protein levels without changes on NFkB. Inhibition of MAPKs did not modify protein levels of NFkB or IkBα. Altogether, these results suggest that the antiproliferative effects of 1,25(OH)2D3 on endothelial cells and SVEC transformed by vGPCR occurred by down-regulation of the NFkB pathway.