The role of the EP receptors for prostaglandin E2 in skin and skin cancer

Abstract

One of the most common features of exposure of skin to ultraviolet (UV) light is the induction of inflammation, a contributor to tumorigenesis, which is characterized by the synthesis of cytokines, growth factors and arachidonic acid metabolites, including the prostaglandins (PGs). Studies on the role of the PGs in non-melanoma skin cancer (NMSC) have shown that the cyclooxygenase-2 (COX-2) isoform of the cyclooxygenases is responsible for the majority of the pathological effects of PGE(2). In mouse skin models, COX-2 deficiency significantly protects against chemical carcinogen- or UV-induced NMSC while overexpression confers endogenous tumor promoting activity. Current studies are focused on identifying which of the G protein-coupled EP receptors mediate the tumor promotion/progression activities of PGE(2) and the signaling pathways involved. As reviewed here, the EP1, EP2, and EP4 receptors, but not the EP3 receptor, contribute to NMSC development, albeit through different signaling pathways and with somewhat different outcomes. The signaling pathways activated by the specific EP receptors are context specific and likely depend on the level of PGE(2) synthesis, the differential levels of expression of the different EP receptors, as well as the levels of expression of other interacting receptors. Understanding the role and mechanisms of action of the EP receptors potentially offers new targets for the prevention or therapy of NMSCs.

Fig. 1

Canonical signaling pathways activated by the EP receptors for PGE₂. EP1 activates phospholipase C (PLC), resulting in the production of 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP ₃). DAG activates protein kinase C (PKC) while IP₃ mobilizes Ca²⁺. EP2 activates adenylate cyclase (AC) which results in elevated cAMP synthesis and protein kinase A (PKA) activation. EP3 negatively regulates AC and thus cAMP levels are reduced. EP4 activates both the AC/cAMP pathway and the PI3K/AKT pathway. The activation of these signaling pathways by the EP receptors in skin results in biological changes that are associated with the promotion and progression of NMSC

Fig. 2

EP1 signaling in keratinocytes. Ligand activation of the EP1 receptor causes conformation changes resulting in activation of the heterotrimeric G protein, Gq. Activation causes release of GDP from the Gα subunit and the binding of GTP, which is associated with release of Gβγ and activation of phospholipase C beta (PLCβ). Activated PLCβ hydrolyzes phosphatidyl inositol 4,5-bisphosphate to 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP ₃). IP₃ raises cytoplasmic Ca²⁺ levels via movement from endoplasmic reticulum stores, leading to activation of calcium signaling pathways. DAG activates protein kinase C (PKC), which subsequently activates the MAPK pathway via Raf-1 activation. PKC can also be activated by the phorbol ester tumor promoters; chronic activation of EP1 may confer tumor promoting/progression activity through PKC

Fig. 3

EP2 signaling in keratinocytes. Ligand activation of the EP2 receptor causes the activation of at least several signaling pathways. Receptor activation results in conformational changes causing a loss of GDP from the α subunit of the Gs protein and binding of GTP, which leads to activation of membrane bound adenylate cyclase (AC). Activation of AC results in the conversion of adenosine triphosphate into cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA). PKA is responsible for activating, via phosphorylation, the transcription factor CREB and the signaling factor ERK1/2. Activation of EP2 can also lead to the formation of a β-arrestin1-Src complex, with subsequent activation of the epidermal growth factor receptor (EGFR). Activation of EGFR causes activation of both the ERK1/2 (MAPK) and AKT pathways. The activation of downstream components of these 3 pathways leads to increased survival (p-Bad), increased proliferation (Cyclin D1), angiogenesis (VEGF) and inflammation (COX-2), all of which contribute to tumorigenesis

Fig. 4

EP4 signaling in keratinocytes. Similar to the EP2 receptor, ligand activation of EP4 also leads to activation of adenylate cyclase (AC) with subsequent formation of cAMP and activation of the transcription factor CREB, although the extent of cAMP formation is significantly less than that resulting from EP2 activation. Although the mechanisms are not understood, activation of the EP4 receptor causes activation of the PI3K and AKT pathway. Thus, the biological outcomes of EP2 vs. EP4 activation are somewhat different, although both contribute to the development of skin cancer