Down-regulation of COX-2 activity by 1α,25(OH)2D3 is VDR dependent in endothelial cells transformed by Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor
Cinthya Tapia,
Fernando Zamarreño,
Gabriela Alejandra Salvador,
Cecilia Irene Casali,
Juan Viso,
María del Carmen Fernandez,
John H. White,
Verónica González-Pardo
Affiliations
Cinthya Tapia
Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia-Universidad Nacional del Sur (UNS), Argentina
Fernando Zamarreño
Instituto de Física del Sur (IFISUR), Departamento de Física, Universidad Nacional del Sur (UNS), CONICET, Bahía Blanca, Argentina
Gabriela Alejandra Salvador
Departamento de Biología, Bioquímica y Farmacia-Universidad Nacional del Sur (UNS), Argentina; Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina
Cecilia Irene Casali
Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Buenos Aires, Argentina; Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini (IQUIFIB)-Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina
Juan Viso
Instituto de Física del Sur (IFISUR), Departamento de Física, Universidad Nacional del Sur (UNS), CONICET, Bahía Blanca, Argentina
María del Carmen Fernandez
Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Cátedra de Biología Celular y Molecular, Buenos Aires, Argentina; Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini (IQUIFIB)-Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina
John H. White
Department of Physiology, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada
Verónica González-Pardo
Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia-Universidad Nacional del Sur (UNS), Argentina; Corresponding author.
Our previous reports showed that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) has antiproliferative actions in endothelial cells stably expressing viral G protein-coupled receptor (vGPCR) associated with the pathogenesis of Kaposi's sarcoma. It has been reported that COX-2 enzyme, involved in the tumorigenesis of many types of cancers, is induced by vGPCR. Therefore, we investigated whether COX-2 down-regulation is part of the growth inhibitory effects of 1α,25(OH)2D3. Proliferation was measured in presence of COX-2 inhibitor Celecoxib (10–20 μM) revealing a decreased in vGPCR cell number, displaying typically apoptotic features in a dose dependent manner similarly to 1α,25(OH)2D3. In addition, the reduced cell viability observed with 20 μM Celecoxib was enhanced in presence of 1α,25(OH)2D3. Remarkably, although COX-2 mRNA and protein levels were up-regulated after 1α,25(OH)2D3 treatment, COX-2 enzymatic activity was reduced in a VDR-dependent manner. Furthermore, an interaction between COX-2 and VDR was revealed through GST pull-down and computational analysis. Additionally, high-affinity prostanoid receptors (EP3 and EP4) were found down-regulated by 1α,25(OH)2D3. Altogether, these results suggest a down-regulation of COX-2 activity and of prostanoid receptors as part of the antineoplastic mechanism of 1α,25(OH)2D3 in endothelial cells transformed by vGPCR.
