Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets?

Abstract

Elevated expression of COX-2 and increased levels of PGE2 are found in numerous cancers and are associated with tumour development and progression. Although epidemiological, clinical and preclinical studies have shown that the inhibition of PGE2 synthesis through the use of either non-steroidal anti-inflammatory drugs (NSAIDs) or specific COX-2 inhibitors (COXibs) has the potential to prevent and treat malignant disease, toxicities due to inhibition of COX-2 have limited their use. Thus, there is an urgent need for the development of strategies whereby COX-2 activity may be reduced without inducing any side effects. The biological effects of PGE2 are mediated by signalling through four distinct E-type prostanoid (EP) receptors - EP1 , EP2 , EP3 and EP4 . In recent years, extensive effort has gone into elucidating the function of PGE2 and the EP receptors in health and disease, with the goal of creating selective inhibitors as a means of therapy. In this review, we focus on PGE2 , and in particular on the role of the individual EP receptors and their signalling pathways in neoplastic disease. As knowledge concerning the role of the EP receptors in cancer grows, so does the potential for exploiting the EP receptors as therapeutic targets for the treatment of cancer and metastatic disease.

Figure 1

Prostaglandin E₂ biosynthesis. Following its release from cellular membranes through the actions of phospholipase A₂ family members, arachidonic acid is converted to PGH₂ through the activity of the COX enzymes. COX‐1 is constitutively expressed at basal levels in many cells, generating low levels of PGs that are cytoprotective and maintain homeostasis. In contrast, COX‐2 is normally absent from most cells but is induced in response to a variety of stimuli including growth factors and cytokines. PGH₂ is rapidly converted to PGE₂ by one of three PGE₂ synthases – cPGES, mPGES‐1 or mPGES‐2. PGE₂ is degraded, in turn, into 15‐keto PGE₂ by 15‐PGDH. PGE₂ signals through four GPCRs, EP₁, EP₂, EP₃ and EP₄. NSAIDs and COXibs, which block the activity of the COX enzymes, and inhibitors of the PGE₂ synthases can potentially suppress the pro‐tumorigenic effects of PGE₂ by reducing its synthesis. Alternatively, targeting the individual EP receptors may suppress the activity of PGE₂.

Figure 2

Canonical signalling pathways activated by the EP receptors. The EP receptors are high‐affinity GPCRs characterized by the activation of different signalling pathways. (A) EP₁ receptors couple to Gαq protein and mediate signalling events by activation of PLC. This results in the elevation of cytoplasmic signalling intermediates including IP3 and DAG, an increase in intracellular Ca²⁺, leading to the activation of PKC. (B) and (C) EP₂ and EP₄ receptors are linked to Gαs proteins and function by inducing the adenylate cyclase (AC) system, increasing the level of the secondary messenger cAMP and activating PKA. The receptors can also activate the PI3K signalling pathway by phosphorylation induced by GPCR kinases. This ultimately results in the triggering of NF‐κB‐mediated transcription programmes. (D) The EP₃ receptors are unique in their ability to couple to multiple G proteins. Activation of Gi proteins results in the inhibition of adenylate cyclase, whereas signalling through Gs results in cAMP production. EP₃ receptors can also be coupled to G_12/13 proteins, resulting in the activation of the small G protein Rho.

Figure 3

Transactivation of the EGFR by PGE₂. Signalling through the EP₁, EP₂ or EP₄ receptors by PGE₂ activates c‐Src, which in turn activates the EGFR, either directly via phosphorylation or indirectly through the induction of MMP activity. Cleavage of the pro‐form of TGFα releases the active TGFα, the ligand for EGFR. Activation of c‐Src by the EP₂ and EP₄ receptors may involve the recruitment of β‐arrestin1 to the receptor. This triggers the dephosphorylation of β‐arrestin, thus allowing its association with c‐Src, with β‐arrestin1 subsequently activating c‐Src.