The tumor promoting activity of the EP4 receptor for prostaglandin E₂ in murine skin

Abstract

Pharmacological and genetic approaches have shown that prostaglandins (PGs) synthesized by cyclooxygenase-2 (COX-2) have tumor promoting/progression activity in murine skin. To determine whether the EP4 receptor for PGE2 contributes to this tumor promoting/progression activity, EP4 over-expressing mice (BK5.EP4) were generated and subjected to several carcinogenesis protocols. A two-stage 7,12-dimethylbenz[a]anthracene (DMBA)-12-O-tetradecanoylphorbol- 13-acetate (TPA) protocol resulted in 25-fold more squamous cell carcinomas (SCCs) in the BK5.EP4 mice than wild type (WT) mice. A similar increase in SCCs was observed following treatment with DMBA alone (no TPA) and following UV irradiation. DMBA caused a cytotoxicity in BK5.EP4, but not WT mice, that was characterized by increased apoptosis, increased metalloproteinase(MMP)-9 and MMP-7 expression, and sloughing of the interfollicular epidermis, followed by regeneration and SCC development. An analysis of cytochrome P450 levels, wound healing time and keratinocyte stem cells showed no difference between BK5.EP4 and WT mice. A comparison of transcriptomes between BK5.EP4 and WT mice treated with PGE2 showed a significant upregulation of a number of genes known to be associated with tumor development, including interleukin-20 (IL-20), which was verified at the protein level, supporting a pro-tumorigenic role for the EP4 receptor.

Differential expression of E-type prostanoid receptors 2 and 4 in microglia stimulated with lipopolysaccharide

“…EP4 receptor signaling attenuates brain inflammation [18] and exerts inhibitory effects on LPS-induced NFκB signaling [30]. However, EP4 activation promotes LPS-induced IL-23 secretion in immature dendritic cells and IL-17 production in activated T cells [31], and exerts pro-tumorigenic actions [32]. Therefore, modulation of EP4 activation in vivo can potentially exert benefits by attenuating the degree of innate immune responses in naïve microglia, but its various actions in different cell types could be detrimental or beneficial depending on the type and stage of disease.…”

New insights into the functions of Cox-2 in skin and esophageal malignancies

“…Prostaglandin E 2 is known to bind and activate its G protein-coupled receptors, prostaglandin E 2 receptors 1 to 4 (known as EP 1 , EP 2 , EP 3, and EP 4 ). The tumor-promoting role of Cox-2 can partly work through each EP receptor, and inhibition of the receptor pathways has the potential to prevent cutaneous SCCs [52][53][54][55] . For example, Tober et al reported suppressed UV-induced skin tumor formation by treatment with the specific EP 1 antagonist ONO-8713 52 .…”

Treatment of actinic keratosis through inhibition of cyclooxygenase‐2: Potential mechanism of action of diclofenac sodium 3% in hyaluronic acid 2.5%

“…Several studies in murine models have demonstrated the importance of COX-1, COX-2, PGE 2 , and PGE 2 receptors for skin tumor development and growth (Fischer, Pavone, Mikulec, Langenbach, & Rundhaug, 2007;Morita, 2002;Simper et al, 2014;Sung, He, Hwang, & Fischer, 2006;Tiano et al, 2002;Tober et al, 2006;Zelenay et al, 2015). Targeted disruptions of the genes encoding either COX-1 or COX-2 led to altered epidermal keratinocyte differentiation and reduced skin tumorigenesis in a multistage mouse skin model (Tiano et al, 2002).…”