1alfa,25-dihydroxyvitamin D3 and its TX527 analog inhibit the growth of endothelial cells transformed by Kaposi sarcoma-associated herpes virus G protein coupled receptor in vitro and in vivo

VERONICA GONZALEZ PARDO; DANIEL MARTIN; SILVIO J GUTKIND; ANNEMIEKE VERSTUYF; ROGER BOUILLON; RICARDO BOLAND; ANA RUSSO DE BOLAND

ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2010 vol. 151 p. 23 - 31

0013-7227

The Kaposi sarcoma-associated herpes virus-G protein-coupled receptor is a key molecule in the pathogenesis of Kaposi sarcoma, playing a central role in promoting vascular endothelial growth factor-driven angiogenesis and spindle cell proliferation. We studied the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the analog TX527 on the proliferation of endothelial cells (SVECs) and SVECs transformed by the viral G protein-coupled receptor (SVEC-vGPCR). 1,25(OH)2D3 and TX527 decreased SVEC-vGPCR and SVEC numbers, the response being time dependent and similar in both cell lines. Vitamin D receptor (VDR) levels increased on treatment with 10 nM 1,25(OH)2D3 or 1 nM TX527 in a time-dependent manner (1.5–24 h) in SVECs and SVEC-vGPCR. Basal VDR levels were increased in SVEC-vGPCR. The antiproliferative effects were accompanied by reduction in cyclin D1 and accumulation of p27 in SVECs but not SVEC-vGPCR. Induction of VDR was blocked by transfection of short hairpinRNAagainst VDR in SVEC-vGPCR and the antiproliferative effects of 1,25(OH)2D3 and TX527 were decreased, involving the VDR genomic pathway in the hormone and analog mechanism of action. In vivo experiments showed that 1,25(OH)2D3 and TX527 decreased SVEC-vGPCR tumor progression when the tumor cells were implanted in nude mice. In conclusion, we have demonstrated that 1,25(OH)2D3 and its TX527 analog have antiproliferative effects on the growth of endothelial cells transformed by the vGPCR in vitro and in vivo, the vitamin D receptor being part of the inhibitory mechanism of action.