1,25(OH)2D3 and analog inhibit the growth of transformed (Kaposi Sarcoma) endothelial cells.

VERONICA GONZALEZ PARDO; DANIEL MARTIN; SILVIO J. GUTKIND; MARIA MARTA FACCHINETTI; RICARDO BOLAND; ANA RUSSO DE BOLAND

Villa Carlos Paz, Cordoba, Argentina

Congreso; XLIV Reunion Anual de la Sociedad Argentina de Investigacion en Bioquimica y Biologia Molecular; 2008

SAIB

The Kaposi sarcoma-associated herpesvirus G protein-coupled receptor (KSHV-GPCR) is a key molecule in the pathogenesis of Kaposi sarcoma, playing a central role in the promotion of vascular endothelial growth factor driven angiogenesis and spindle cell proliferation. In this work we have studied the effects of 1á,25(OH)2D3 (1,25D) and its TX527 analog on the proliferation of endothelial cells (EC) and transformed by viral GPCR (vGPCR). Proliferation assays showed that 1,25D and TX527 similarly decreased EC-vGPCR and EC cell number. VDR protein levels were induced by 1,25D or TX527 in time and dose-dependent fashion. In addition, basal VDR levels were increased in EC-vGPCR. The antiproliferative effects were also accompanied by a reduction in cyclin D1 levels and an accumulation of p27 monitored by WB analysis in EC but not in endothelial vGPCR. Induced VDR protein levels were blocked by stable transfection of shRNA against VDR in EC-vGPCR and the antiproliferative effect was decreased, demonstrating, that at least in part, the genomic pathway through VDR is involved in hormone and TX527 mechanism of action. In vivo experiments have shown the ability of 1,25D and TX527 to decrease EC-vGPCR tumor progression when the tumor cells were implanted in female nude mice. Although 1,25D was more successful than TX527 to inhibit tumor growth in vivo; TX527 was less calcemic and make it more suitable for its potential use as therapeutic strategy for Kaposi sarcoma treatment.