title: Cell cycle arrest and apoptosis induced by 1α,25(OH)2D3 and TX 527 in Kaposi sarcoma is VDR dependent.
abstract: We have previously shown that 1α,25(OH)2-Vitamin D3 [1α,25(OH)2D3] and its less calcemic analog TX 527 inhibit the proliferation of endothelial cells transformed by the viral G protein-coupled receptor associated to Kaposi sarcoma (vGPCR) and this could be partially explained by the inhibition of the NF-κB pathway. In this work, we further explored the mechanism of action of both vitamin D compounds in Kaposi sarcoma. We investigated whether the cell cycle arrest and subsequent apoptosis of endothelial cells (SVEC) and SVEC transformed by vGPCR (SVEC-vGPCR) elicited by 1α,25(OH)2D3 and TX 527 were mediated by the vitamin D receptor (VDR). Cell cycle analysis of SVEC and SVEC-vGPCR treated with 1α,25(OH)2D3 (10nM, 48h) revealed that 1α,25(OH)2D3 increased the percentage of cells in the G0/G1 phase and diminished the percentage of cells in the S phase of the cell cycle. Moreover, the number of cells in the S phase was higher in SVEC-vGPCR than in SVEC due to vGPCR expression. TX 527 exerted similar effects on growth arrest in SVEC-vGPCR cells. The cell cycle changes were suppressed when the expression of the VDR was blocked by a stable transfection of shRNA against VDR. Annexin V-PI staining demonstrated apoptosis in both SVEC and SVEC-vGPCR after 1α,25(OH)2D3 and TX 527 treatment (10nM, 24h). Cleavage of caspase-3 detected by Western blot analysis was increased to a greater extent in SVEC than in SVEC-vGPCR cells, and this effect was also blocked in VDR knockdown cells. Altogether, these results suggest that 1α,25(OH)2D3 and TX 527 inhibit the proliferation of SVEC and SVEC-vGPCR and induce apoptosis by a mechanism that involves the VDR.
authors: Departamento de Biología, Bioquímica & Farmacia, Universidad Nacional del Sur-CONICET, 8000 Bahía Blanca, Argentina. Electronic address: vgpardo@criba.edu.ar.
authors: Verónica
authors: V
authors: González-Pardo
authors: Departamento de Biología, Bioquímica & Farmacia, Universidad Nacional del Sur-CONICET, 8000 Bahía Blanca, Argentina.
authors: Alejandra
authors: A
authors: Suares
authors: Laboratory of Clinical and Experimental Endocrinology, KU Leuven, B-3000 Leuven, Belgium.
authors: Annemieke
authors: A
authors: Verstuyf
authors: Vakgroep Organische Chemie, Universiteit Gent, Krijgslaan 281 S4, B-9000 Gent, Belgium.
authors: Pierre
authors: P
authors: De Clercq
authors: Departamento de Biología, Bioquímica & Farmacia, Universidad Nacional del Sur-CONICET, 8000 Bahía Blanca, Argentina.
authors: Ricardo
authors: R
authors: Boland
authors: Departamento de Biología, Bioquímica & Farmacia, Universidad Nacional del Sur-CONICET, 8000 Bahía Blanca, Argentina.
authors: Ana Russo
authors: AR
authors: de Boland
mesh_terms: D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002117:Calcitriol / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002762:Cholecalciferol / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D018167:Receptors, Calcitriol / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
chemical_list: D000480:Alkynes; D050071:Bone Density Conservation Agents; D018167:Receptors, Calcitriol; C409043:inecalcitol; D002762:Cholecalciferol; D002117:Calcitriol
keywords: 1α,25(OH)(2)D(3); Apoptosis; Kaposi sarcoma; TX 527; VDR