Title | KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Medina MVictoria, Agostino AD, Ma Q, Eroles P, Cavallin L, Chiozzini C, Sapochnik D, Cymeryng C, Hyjek E, Cesarman E, Naipauer J, Mesri EA, Coso OA |
Journal | PLoS Pathog |
Volume | 16 |
Issue | 10 |
Pagination | e1009006 |
Date Published | 2020 10 |
ISSN | 1553-7374 |
Keywords | Animals, Carcinogenesis, Cell Transformation, Neoplastic, Endothelial Cells, GTP-Binding Proteins, Herpesvirus 8, Human, MAP Kinase Signaling System, Matrix Metalloproteinase 2, Mice, Mice, Nude, Neovascularization, Pathologic, NIH 3T3 Cells, Oncogenes, Receptors, G-Protein-Coupled, Sarcoma, Kaposi, Signal Transduction, Transcriptional Activation |
Abstract | 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. |
DOI | 10.1371/journal.ppat.1009006 |
Alternate Journal | PLoS Pathog |
PubMed ID | 33057440 |
PubMed Central ID | PMC7591070 |
Grant List | R01 CA136387 / CA / NCI NIH HHS / United States U54 CA221208 / CA / NCI NIH HHS / United States |
Related Faculty:
Ethel Cesarman, M.D., Ph.D.