Figure 1

The synthesis, control of tissue level and signalling pathways for PGE ₂ is presented. The control of tissue level of PGE₂ is both through synthesis of PGE₂ by the COX enzyme in and its export from pro-inflammatory cells as well as by the removal of PGE₂ from the intercellular space by prostaglandin transporter, PGT, and the efficiency of catabolism of PGE₂ by enzymes such as 15-prostaglandin dehydrogenease. For instance, expression of the COX-2 enzyme is regulated through many pathways of which several are affected in CRC. As examples of this, somatostatin, SS, has a dampening effect on COX-2 expression, while an autocrine pathway through an epidermal growth factor receptor, EGFR, an EP4 receptor, and microRNA stimulation increase the expression and/or activity of the enzyme. Furthermore, the activity in PGE₂-signalling pathways may vary with the expression of the PGE₂ receptor subtypes, EP1, EP2, EP3 and EP4, which is affected in CRC. Removal of PGE₂ from the extracellular compartment around target cells is by diffusion to the blood stream and uptake and degradation in lung, liver and kidney endothelial cells. Different cellular signalling pathways for PGE₂ operation are indicated in the target cell. The activity in various short-term and long-term pathways, as indicated in the target cell, is increased with the CRN/CRC conditions and therefore affecting a host of cell responses, including ion secretion. "Various responses" as mentioned in the figure refers to differentiation, proliferation, survival/apoptosis, exocrine secretion, altered immune response, invasiveness/metastasis, angiogenesis. Abbreviations: AA = arachidonic acid, CBR = carbonyl reductase - also involved in degradation of PGE₂, COX1/2 = cyclooxygenase isoforms 1 and 2, EGFR = epidermal growth factor receptor, GPCR = G protein-coupled receptors, miRNA = microRNA, MRP4 = multi-drug resistance related polypeptide 4 - example of an ABC export pump, 15-PGDH = 15-prostaglandin dehydrogenase, PGT = prostaglandin transporter, PL = phospholipid, PLA₂ = phospholipase A₂, RTK = tyrosine kinase receptor pathway, SS = somatostatin, sst3/5 = somatostatin subtype receptor 3 or 5.