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

TAPIA, CINTHYA; CASALI, CECILIA IRENE; WHITE, JOHN H.; SALVADOR, GABRIELA ALEJANDRA; FERNANDEZ, MARÍA DEL CARMEN; ZAMARREÑO, FERNANDO; VISO, JUAN; GONZÁLEZ-PARDO, VERÓNICA

Heliyon

Elsevier Ltd

Año: 2020 vol. 6

2405-8440

1α,25(OH)2D3; VDR; COX-2; Kaposi´s sarcoma; Biocomputational method; Biochemistry; Cancer research; Toxicology; Oncology.Our previous reports showed that 1α,25-Dihydroxy-vitamin D3 (1α,25(OH)2D3) has antiproliferative actions in endothelial cells stably expressing viral G protein-coupled receptor (vGPCR) associated to 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 by 1α,25(OH)2D3 is part of its growth inhibitory effects. 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.