Vitamin D agonists and proteasome inhibition upregulate Bim protein in endothelial cells

ALEJANDRA SUARES; ANA RUSSO DE BOLAND; MIEKE VERSTUYF; RICARDO BOLAND; VERONICA GONZALEZ PARDO

Rosario

Congreso; L Reunion Anual de SAIB; 2014

SAIB

The pro-apoptotic Bim (Bcl-2 interacting mediator of cell death) is a key regulator of tissue homeostasis. We have previously shown that vitamin D agonists, 1α,25(OH)2-Vitamin D3 [1α,25(OH)2D3] and its less calcemic analog TX 527 inhibit the proliferation of endothelial cells (SVEC) and transformed by the viral G protein-coupled receptor associated to Kaposi sarcoma (vGPCR) inducing Bim expression and apoptosis. Bim expression can be controlled by transcriptional and post-transcriptional mechanisms. We further explored the mechanism of regulation of Bim and the role of vitamin D receptor (VDR) in its expression. We found that increasing Bim by 1α,25(OH)2D3 or TX 527 was suppressed when VDR expression was blocked by stable transfection of shRNA against VDR. Bortezomib, a proteasome inhibitor used to inhibit NFkB pathway highly activated in vGPCR cells, similarly to vitamin D agonists, also increased Bim protein levels in a dose-dependent manner (0.25-1 nM). This was accompanied by a reduction in the phosphorylation state of Akt and ERK1/2. Moreover, FOXO3a phosphorylation was also decreased in vGPCR cells. Since Bim increase can be regulated by Akt/FOXO3a pathway and by reduction of its degradation by inhibition of ERK, these results suggest that vitamin D agonists-dependent Bim increment might be regulated by the inhibition of ERK and Akt in SVEC and vGPCRs cells