Cyclooxygenase-2-prostaglandin E2-eicosanoid receptor inflammatory axis: a key player in Kaposi's sarcoma-associated herpes virus associated malignancies

Abstract

The role of cyclooxygenase-2 (COX-2), its lipid metabolite prostaglandin E2 (PGE2), and Eicosanoid (EP) receptors (EP; 1-4) underlying the proinflammatory mechanistic aspects of Burkitt's lymphoma, nasopharyngeal carcinoma, cervical cancer, prostate cancer, colon cancer, and Kaposi's sarcoma (KS) is an active area of investigation. The tumorigenic potential of COX-2 and PGE2 through EP receptors forms the mechanistic context underlying the chemotherapeutic potential of nonsteroidal anti-inflammatory drugs (NSAIDs). Although role of the COX-2 is described in several viral associated malignancies, the biological significance of the COX-2/PGE2/EP receptor inflammatory axis is extensively studied only in Kaposi's sarcoma-associated herpes virus (KSHV/HHV-8) associated malignancies such as KS, a multifocal endothelial cell tumor and primary effusion lymphoma (PEL), a B cell-proliferative disorder. The purpose of this review is to summarize the salient findings delineating the molecular mechanisms downstream of COX-2 involving PGE2 secretion and its autocrine and paracrine interactions with EP receptors (EP1-4), COX-2/PGE2/EP receptor signaling regulating KSHV pathogenesis and latency. KSHV infection induces COX-2, PGE2 secretion, and EP receptor activation. The resulting signal cascades modulate the expression of KSHV latency genes (latency associated nuclear antigen-1 [LANA-1] and viral-Fas (TNFRSF6)-associated via death domain like interferon converting enzyme-like- inhibitory protein [vFLIP]). vFLIP was also shown to be crucial for the maintenance of COX-2 activation. The mutually interdependent interactions between viral proteins (LANA-1/vFLIP) and COX-2/PGE2/EP receptors was shown to play key roles in the biological mechanisms involved in KS and PEL pathogenesis such as blockage of apoptosis, cell cycle regulation, transformation, proliferation, angiogenesis, adhesion, invasion, and immune-suppression. Understanding the COX-2/PGE2/EP axis is very important to develop new safer and specific therapeutic modalities for KS and PEL. In addition to COX-2 being a therapeutic target, EP receptors represent ideal targets for pharmacologic agents as PGE2 analogues and their blockers/antagonists possess antineoplastic activity, without the reported gastrointestinal and cardiovascular toxicity observed with few a NSAIDs.

Altering the Anti-inflammatory Lipoxin Microenvironment: a New Insight into Kaposi's Sarcoma-Associated Herpesvirus Pathogenesis

“…Our studies show a decrease in the levels of these host proteins upon lipoxin and epilipoxin treatment. Previous studies from our research group have shown that several proinflammatory factors of the arachidonic acid pathway, such as COX-2, PGE2, 5-lipoxygenase, and LTB4, are upregulated during KSHV infection (10,14,35). These proinflammatory arachidonic acid metabolites have been shown to enhance KSHV latency, pathogenesis, and immune evasion and to promote an inflammatory microenvironment (10,14,35).…”

“…Several proinflammatory metabolites of the arachidonic acid pathway, such as COX-2/ PGE2 and 5-lipoxygenase/LTB4, were upregulated on KSHV infection (14,35). To study the KSHV infection mediated alteration of the anti-inflammatory lipoxin secretion pathway, an ELISA was performed on supernatants from KSHV-infected and uninfected HMVEC-d cells.…”

“…KSHV utilizes its latency cluster containing ORF73 (latency-associated nuclear antigen 1 [LANA-1]), ORF72 (viral cyclin [vCyclin]), ORF71 (K13/ vFLIP), and ORFK12 (kaposins A, B, and C), as well as 12 distinct pre-microRNAs, to modulate the host immune system and maintain lifelong latency (7-9). KSHV also encodes several homologs of cytokines and chemokines to alter the immune response (6).KSHV induces several proinflammatory host molecules such as COX-2/PGE2, 5-lipoxygenase, and LTB4 to establish latency and aid in its pathogenesis (10)(11)(12)(13)(14). Beside upregulating proinflammatory pathways, KSHV also modulates the immune system by downregulating anti-inflammatory pathways (15).…”

“…KSHV induces several proinflammatory host molecules such as COX-2/PGE2, 5-lipoxygenase, and LTB4 to establish latency and aid in its pathogenesis (10)(11)(12)(13)(14). Beside upregulating proinflammatory pathways, KSHV also modulates the immune system by downregulating anti-inflammatory pathways (15).…”

Activated Nrf2 Interacts with Kaposi's Sarcoma-Associated Herpesvirus Latency Protein LANA-1 and Host Protein KAP1 To Mediate Global Lytic Gene Repression

“…The induction of COX-2 during KSHV infection and its signaling through PGE2 production have been thoroughly investigated (40,(55)(56)(57)(58)(59)(60). In our recent reports, we determined that Nrf2 induction during de novo KSHV infection of endothelial cells (HMVEC-d) was important for transcriptional upregulation of COX-2 expression (30,61).…”