Signalling networks in focusSignalling networks regulating cyclooxygenase-2
Introduction
Arachidonic acid (5,8,11,14-eicosatetraenoic acid), a polyunsaturated fatty acid, is stored within the cell membrane, esterified to glycerol in phospholipids and is subsequently released following deacylation by phospholipases (Warner & Mitchell, 2004). Arachidonic acid functions as substrate for the cyclooxygenase (COX) (prostaglandin G/H synthase) enzymes, which transform it to eicosanoids. First, arachidonic acid is transformed to the short-lived intermediates prostaglandin G2 and prostaglandin H2, which are transformed to either prostaglandins (via prostaglandin isomerases), prostacyclin (via prostacyclin synthase) or thromboxane (via thromboxane synthase) (Mindrescu, Le, Wisniewski, & Vilcek, 2005).
COX-1 and COX-2 catalyze the rate-limiting step in the formation of prostaglandins (Ramsay, Ciznadija, Vanevski, & Mantamadiotis, 2003). COX-1 and COX-2 share a 60% homology. COX-1 is constitutively expressed in most cells, thus regarded as a housekeeping molecule. On the other hand, the expression of COX-2 is inducible and remains undetectable in most mammalian tissues under basal conditions. Exposure of several types of cells including fibroblasts, endothelial cells and monocytes to bacterial endotoxins, cytokines, hormones or growth factors induces its expression within 2–6 h. Glucocorticoids are powerful suppressors of COX-2 synthesis at the transcriptional and post transcriptional level (Smith, Garavito, & DeWitt, 1996). In few organs including the central nervous system kidneys and the gonads, COX-2 is expressed in a constitutive manner similar to COX-1. It should be noted that COX-1 promoter lacks TATA and CAAT box while it is rich in GC, features consistent with those of a housekeeping gene. COX-2 is also regulated at the post-transcriptional and at the enzymatic levels. A modulator of COX-2 activity is NO affecting directly its enzymatic activity (Mitchell, Larkin, & Williams, 1995). NO exhibits high affinity to iron containing enzymes, which is the case for COX-2 that contains an iron heme center in its catalytic domain (Kurumbail, Kiefer, & Marnett, 2001). COX-2 is ten times more sensitive to activation by hydroperoxide compared to COX-1. Thus, low levels of peroxide may only induce COX-2 activity and not COX-1 (Kulmacz & Wang, 1995).
This review focuses on the positive and negative signalling cascades controlling COX-2 expression and activity and provides insight on its role in inflammation, cell growth and cancer biology. Given the controversy on the therapeutic value of the selective COX-2 inhibitors, a better understanding of the signalling networks that regulate COX-2 expression and catalytic activity is necessary for designing novel anti-inflammatory compounds.
Section snippets
Physiological role of COX-2; lessons from knockout mice
Data from COX-2 deficient mice provide interesting information about the crucial physiological role of this enzyme (Langenbach, Loftin, Lee, & Tiano, 1999; Loftin, Tiano, & Langenbach, 2002). Indeed, COX-2 appears to be of paramount importance for neonatal survival (Loftin et al., 2001). COX-2 knockout mice are susceptible to peritonitis, they develop congestive heart failure from cardiac fibrosis, in at least 50% of animals, and they develop severe malfunction of the signalling pathway in the
Lipopolysaccharide (LPS) signalling
Historically, gram (−) bacterial LPS was the first inducer of COX-2 expression to be identified in macrophages (Lee et al., 1992). It is now known that most pro-inflammatory mediators induce the expression of COX-2. More specifically, LPS and other TLR ligands bind to MyD88-associated receptors and via MEK/ERK induce the transcription factor activator protein 1 (AP1). LPS also activates the TRAF6/NIK/Tpl2/IKK/NFkB pathway, which also leads to induction of COX-2 transcription. Tpl2 signals also
COX-2 in chronic inflammatory diseases and atherosclerosis
COX-2 is known to be over-expressed in the synovia of patients with rheumatoid arthritis, osteoarthritis and in the colonic epithelium in ulcerative colitis. Atherosclerosis is now considered a chronic inflammatory disease, a consequence of a pathological interaction between vascular endothelial and immune cells. COX-2 is upregulated in stimulated macrophages during exposure to high levels of oxLDL and in oxLDL-induced foam cell formation (Tuomisto, Riekkinen, Viita, Levonen, & Yla-Herttuala,
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2022, PhytomedicineCitation Excerpt :Several cancers are characterized by an increased expression of COX enzymes (Greenhough et al., 2009) and other mediators of inflammation (Eberhart et al., 1994; Liu et al., 2015; Tucker et al., 1999). A number of inflammatory pathways can trigger COX mediated signaling e.g. LPS signaling, nitric oxide signaling, cytokine signaling, and growth factor signaling (Tsatsanis et al., 2006). Non-steroidal anti-inflammatory drugs (NSAIDS) block activity of COX enzymes and are typically used to treat inflammation (Ricciotti and FitzGerald, 2011).