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

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

PLOS Pathogens

PLOS Pathogens

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 toinduce cell transformation in Kaposi?s sarcoma. Cyclooxygenase-2 (COX-2) is an inflammatorymediator that plays a key regulatory role in the activation of tumor angiogenesis. Herebywe demonstrate, using two different transformed mouse models, and tumorigenic full KSHVgenome-bearing cells, including KSHV-Bac16 based mutant system with a vGPCR deletion,that vGPCR upregulates COX-2 expression and activity, signaling through selective MAPKcascades. We show that vGPCR expression triggers signaling pathways that upregulateCOX-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 throughERK1/2 MAPK pathway. Inhibition of COX-2 in vGPCR-transformed cells impairs vGPCR drivenangiogenesis and treatment with the COX-2-selective inhibitory drug Celecoxib producesa significant decrease in tumor growth, pointing to COX-2 activity as critical forvGPCR oncogenicity in vivo and indicating that COX-2-mediated angiogenesis could play arole in KS tumorigenesis. These results, along with the overexpression of COX-2 in KSlesions, define COX-2 as a potential target for the prevention and treatment of KSHVoncogenesis.