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 PGE2. 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 PGE2 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 PGE2 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.

Prostaglandin E2 promotes proliferation of skeletal muscle myoblasts via EP4 receptor activation

“…In contrast, the EP3 receptor inhibits adenylate cyclase by coupling to Gi. 18,19 Nevertheless, the roles of EP subtypes in cell proliferation are different, and could be cell type-dependent. [20][21][22][23][24] To study the role of PGE 2 in myoblast proliferation, the expression of EPs in mouse primary myoblasts was determined showing that all EPs are expressed in myoblasts.…”

COX-2 Inhibitors, a Potential Synergistic Effect with Antineoplastic Drugs in Lung Cancer

“…In cancer, the regulation of COX-2 is abolished, so that both enzymes are overexpressed, leading to an increase in prostaglandin (PGE2) production in these cells [42]. PGE2 via stimulation of prostaglandin E2 receptor activates multiple pathways resulting in tumor cell proliferation, angiogenesis, survival and antiapoptosis [43][44][45][46]. In lung cancer cells, particularly in adenocarcinoma, according to clinical studies, overexpression of COX-2 is considered to be a negative predictive factor in the survival of the subpopulation [47].…”

Prostaglandin E₂ Inhibits Proteinase-Activated Receptor 2-Signal Transduction through Regulation of Receptor Internalization

“…3, that the EP1 or EP2 receptors were involved in the inhibitory effect of PGE 2 . It is well known that the activation of EP2 increases intracellular cAMP but not EP1 [23]. It was also reported that another type of PAR, PAR1, is downregulated by PGE 2 via EP2 [29].…”