1a,25(OH)2-Vitamin 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; ANA RUSSO DE BOLAND; RICARDO BOLAND

Brugge, Belgium

Congreso; 14 th Workshop on Vitamin D; 2009

The Kaposi sarcoma (KS)-associated herpes virus G protein-coupled receptor (KSHV-GPCR) is a key molecule in the pathogenesis of KS, playing a central role in promoting vascular endothelial growth factor-driven angiogenesis and spindle cell proliferation. We studied the effects of 1,25(OH)2 vitamin D3 (1,25D) and the analog TX527 on the proliferation of endothelial cells (SVEC cell line) and SVEC transformed by the viral GPCR (SVEC-vGPCR). 1,25D and TX527 decreased SVEC-vGPCR and SVEC cell numbers, the response being time-dependent and similar in both cell lines. Vitamin D receptor (VDR) levels increased upon treatment with 10 nM 1,25D or 1 nM TX527 in a time-dependent manner (1.5-24 h) in SVEC 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 SVEC but not in SVEC-vGPCR. Induction of VDR was blocked by transfection of shRNA against VDR in SVEC-vGPCR and the antiproliferative effects of 1,25D and TX527 were decreased, involving the VDR genomic pathway in the hormone and analog mechanism of action. In vivo experiments showed that 1,25D and TX527 decreased SVEC-vGPCR tumor progression when the tumor cells were implanted in nude mice. Although 1,25D was more effective than TX527 to inhibit tumor growth in vivo, the analog was less calcemic suggesting that it might be more suitable for KS treatment.