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.
Highlights
Kaposi’s sarcoma (KS) is among the most common type of cancers associated with the Acquired Immunodeficiency Syndrome (AIDS, AIDS-KS) [1,2,3,4]
A gene encoded by the virus expresses a protein with oncogenic potential in the infected cells, which has the ability to promote cell transformation and angiogenesis driving KS tumorigenesis
We show that COX-2 activity is critical for vGPCR angiogenesis and oncogenesis using KS herpesvirus (KSHV) infection and mouse models
Summary
Kaposi’s sarcoma (KS) is among the most common type of cancers associated with the Acquired Immunodeficiency Syndrome (AIDS, AIDS-KS) [1,2,3,4]. VGPCR immortalizes human endothelial cells by autocrine activation of the VEGF receptor [17] and upregulates PDGF expression via a Rac1-NOX-ROS oxidative stress axis [26]. VGPCR has been identified as a major KSHV angiogenesis activating oncogene [18,19,20] that subverts host-cell proliferative and inflammatory signaling cascades leading to tumorigenicity and VEGF-mediated angiogenesis [18,21,22], and it has been shown to produce KS-like angioproliferative lesions in mice [20,23,24,25]. All these facts identify vGPCR, and the molecular components of the proangiogenic signaling pathways that triggers, as targets for preventing and treating KS
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