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

MEDINA VICTORIA; D'AGSOTINO AGATA; QI MA; PILAR EROLES; LUCAS CAVALLIN; CHIARA CHIOZZINI; DAIANA SAPOCHNIK; CORA B. CYMERYNG; ELIZABETH HYJEK; ETHEL CESARMAN; JULIAN NAIPAUER; ENRIQUE MESRI; & OMAR A. COSO

PLOS PATHOGENS

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2020 vol. 10

1553-7366

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. Usingtwo different transformed mouse models and tumorigenic full KSHV genome-bearing cells,including KSHV-Bac16 based mutant system with a vGPCR deletion, we demostrate thatvGPCR 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, the3?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 vGPCRdrivenangiogenesis 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 KS