KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma.
Animals
Carcinogenesis
Cell Transformation, Neoplastic
/ genetics
Endothelial Cells
/ metabolism
GTP-Binding Proteins
/ genetics
Herpesvirus 8, Human
/ genetics
MAP Kinase Signaling System
Matrix Metalloproteinase 2
/ biosynthesis
Mice
Mice, Nude
NIH 3T3 Cells
Neovascularization, Pathologic
/ metabolism
Oncogenes
Receptors, G-Protein-Coupled
/ genetics
Sarcoma, Kaposi
/ blood supply
Signal Transduction
Transcriptional Activation
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
17
02
2020
accepted:
27
09
2020
revised:
27
10
2020
pubmed:
16
10
2020
medline:
26
1
2021
entrez:
15
10
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33057440
doi: 10.1371/journal.ppat.1009006
pii: PPATHOGENS-D-20-00305
pmc: PMC7591070
doi:
Substances chimiques
Receptors, G-Protein-Coupled
0
Matrix Metalloproteinase 2
EC 3.4.24.24
Mmp2 protein, mouse
EC 3.4.24.24
GTP-Binding Proteins
EC 3.6.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009006Subventions
Organisme : NCI NIH HHS
ID : R01 CA136387
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA221208
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing financial interests.
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