title: 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.
authors.affiliation: Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Ill., USA.
authors.forename: Arun George
authors.initials: AG
authors.lastname: Paul
authors.forename: Bala
authors.initials: B
authors.lastname: Chandran
authors.forename: Neelam
authors.initials: N
authors.lastname: Sharma-Walia
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000472:pathogenicity*; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy / Q000378:metabolism*; D018055:Receptors, Eicosanoid / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D015398:Signal Transduction; D017735:Virus Latency / Q000235:genetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D018055:Receptors, Eicosanoid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone
keywords: C-X-C motif; COX-2; CREB; Cellular inhibitor of apoptosis protein-1; EBV; ERK; Epstein-Barr virus; Extracellular signal-regulated kinase; FAK; HTLV; ID4; IFN-γ; KS; KSHV; Kaposi's sarcoma; Kaposi's sarcoma associated-herpes virus; LANA-1; LIM domain only 2; LMO2; LRMP; MYC; MnSOD2; NFAT; NSAIDs; PDGF-β; PEL; PGE2; PI3-K; Phosphatidylinositide 3-kinase; ROS; SDF-1; STAT-1α; Signal transducer and activator of transcription 1-alpha; TGF-b; TLR5; Toll-like receptor 5; Transforming growth factor beta; VCAM-1; VEGF; X-IAP; X-linked inhibitor of apoptosis protein; XCR4; cAMP response element-binding; cIAP-1; chemokine; cyclooxygenase-2; focal adhesion kinase; human lymphotropic virus; inhibitor of DNA binding 4; interferon-g; latency associated nuclear antigen; lymphoid restricted membrane protein; manganese superoxide dismutase; nonsteroid anti-inflammatory drugs; nonsteroidal anti-inflammatory drugs; nuclear factor of activated T cells; platelet derived growth factor β; primary effusion lymphoma; prostaglandin E2; reactive oxygen species; receptor 4; stromal cell-derived factor-1; v-myc myelocytomatosis viral oncogene homolog; vascular endothelial growth factor; vascular-cell adhesion molecules