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

Public Library of Science

Lugar: San Francisco; Año: 2020 vol. 16

Kaposi'ssarcoma-associated herpesvirus (KSHV) vGPCR is a constitutively active Gprotein-coupled receptor that subverts proliferative and inflammatory signalingpathways to induce cell transformation in Kaposi?s sarcoma. Cyclooxygenase-2(COX-2) is an inflammatory mediator that plays a key regulatory role in theactivation of tumor angiogenesis. Hereby we demonstrate, using two differenttransformed mouse models, and tumorigenic full KSHV genome-bearing cells,including KSHV-Bac16 based mutant system with a vGPCR deletion, that vGPCR upregulatesCOX-2 expression and activity, signaling through selective MAPK cascades. Weshow that vGPCR expression triggers signaling pathways that upregulate CPX-2levels due to a dual effect upon both is gene promoter region and, in maturemRNA, the 3?UTR region that control mRNA stability. Both events are mediated bysignaling through ERK1/2 MAPK pathway. Inhibition of COX-2 in vGPCR-transformedcells impairs vGPCR-driven angiogenesis and treatment with the COX-2-selectiveinhibitory drug Celecoxib produces a significant decrease in tumor growth,pointing to COX-2 activity as critical for vGPCR oncogenicity in vivo andindicating that COX-2 mediated angiogenesis could play a role in KStumorigenesis. These results, along with the overexpression of COX-2 in KSlesions, define COX-2 as a potential target for the prevention and treatment ofKSHV-oncogenesis.