KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi’s sarcoma

MEDINA, MARÍA VICTORIA; EROLES, PILAR; SAPOCHNIK, DAIANA; CESARMAN, ETHEL; COSO, OMAR A.; MA, QI; CHIOZZINI, CHIARA; HYJEK, ELIZABETH; MESRI, ENRIQUE A.; MA, QI; CHIOZZINI, CHIARA; HYJEK, ELIZABETH; MESRI, ENRIQUE A.; D´AGOSTINO, AGATA; CAVALLIN, LUCAS; CYMERYNG, CORA; NAIPAUER, JULIAN; D´AGOSTINO, AGATA; CAVALLIN, LUCAS; CYMERYNG, CORA; NAIPAUER, JULIAN; MEDINA, MARÍA VICTORIA; EROLES, PILAR; SAPOCHNIK, DAIANA; CESARMAN, ETHEL; COSO, OMAR A.

PLOS Pathogens

Public Library of Science

Año: 2020 vol. 16

Kaposi´s sarcoma-associated herpesvirus (KSHV) vGPCR is a constitutively active G protein-coupled receptor that subverts proliferative and inflammatory signaling pathways to induce cell transformation in Kaposi´s sarcoma. Cyclooxygenase-2 (COX-2) is an inflammatory mediator that plays a key regulatory role in the activation of tumor angiogenesis. Using two different transformed mouse models and tumorigenic full KSHV genome-bearing cells, including KSHV-Bac16 based mutant system with a vGPCR deletion, we demostrate that vGPCR upregulates COX-2 expression and activity, signaling through selective MAPK cascades. We show that vGPCR expression triggers signaling pathways that upregulate COX-2 levels due to a dual effect upon both its gene promoter region and, in mature mRNA, the 3´UTR region that control mRNA stability. Both events are mediated by signaling through ERK1/2 MAPK pathway. Inhibition of COX-2 in vGPCR-transformed cells impairs vGPCR-driven angiogenesis and treatment with the COX-2-selective inhibitory drug Celecoxib produces a significant decrease in tumor growth, pointing to COX-2 activity as critical for vGPCR oncogenicity in vivo and indicating that COX-2-mediated angiogenesis could play a role in KS tumorigenesis. These results, along with the overexpression of COX-2 in KS lesions, define COX-2 as a potential target for the prevention and treatment of KSHV-oncogenesis.