Role of Modulator of Inflammation Cyclooxygenase-2 in Gammaherpesvirus Mediated Tumorigenesis

Abstract

Chronic inflammation is recognized as a threat factor for cancer progression. Release of inflammatory molecules generates microenvironment which is highly favorable for development of tumor, cancer progression and metastasis. In cases of latent viral infections, generation of such a microenvironment is one of the major predisposing factors related to virus mediated tumorigenesis. Among various inflammatory mediators implicated in pathological process associated with cancer, the cyclooxygenase (COX) and its downstream effector molecules are of greater significance. Though the role of infectious agents in causing inflammation leading to transformation of cells has been more or less well established, however, the mechanism by which inflammation in itself modulates the events in life cycle of infectious agent is not very much clear. This is specifically important for gammaherpesviruses infections where viral life cycle is characterized by prolonged periods of latency when the virus remains hidden, immunologically undetectable and expresses only a very limited set of genes. Therefore, it is important to understand the mechanisms for role of inflammation in virus life cycle and tumorigenesis. This review is an attempt to summarize the latest findings highlighting the significance of COX-2 and its downstream signaling effectors role in life cycle events of gammaherpesviruses leading to progression of cancer.

Keywords: COX-2; gammaherpesvirus; inflammation.

FIGURE 1

Arachidonic acid is converted to prostaglandins by action of cyclooxygenase 1 and 2 Cox-1 and Cox-2 enzymes. Cox-1 is important for maintaining homeostatic functions of body like platelet formation for blood, kidney development and its functions, maintenance of gastric mucosa etc. Cox-2 derived prostaglandin PGE₂ is associated with increased inflammation, increased angiogenesis, greater metastatic and proliferative invasion, reduction in apoptosis and formation of immunosuppressive microenvironment. NSAIDs function as cox inhibitors and serve as effective tool against Cox mediated cancer. Aspirin and several other dual acting NSAIDs, which can block both Cox-1 and Cox-2 pathway, have several limitations and side effects associated with them and thus there was a need to develop Cox-2 specific inhibitors. NSAIDs reduce incidences of cancer by increasing apoptosis of tumor tissue, maintaining anti-tumor microenvironment, reducing proliferation and angiogenesis

FIGURE 2

Schematic model shows that COX-2 upregulation in response to an inflammatory signal can result in gammaherpesvirus lytic reactivation in latently infected cells. The upregulation of COX-2 is associated with gammaherpesvirus lytic cycle reactivation. Inhibition of COX-2 with specific inhibitor NS-398 blocks lytic reactivation. The up regulation of COX-2 results in increased secretion of the downstream effector PGE₂ which works both via autocrine and paracrine mode which is facilitated through EP receptors. The EP1 and EP4 receptors are also upregulated and their inhibition reduces viral lytic reactivation. Also, PGE₂ released from inflamed distant epithelial cell also can act via a paracrine mode of action and lead to virus lytic reactivation in co-cultivated latently infected cell.