Article Figures & Data
Figures
- Figure 1.
The five main PG species produced from the PG synthesis pathway with their cognate cell surface receptors. Plasma membrane–derived arachidonic acid, which is produced by phospholipase A2, is converted by either of the two COX isoforms (COX-1 or COX-2) into PGH2. Subsequently, PGH2 is converted to a series of PG end products by specific PG synthases (e.g., PGE synthase). There are at least three PGE synthase isoforms (cytosolic PGE synthase and microsomal PGE synthase-1 and PGE synthase-2) that couple functionally to individual upstream COX isoforms (3). For example, inducible microsomal PGE synthase-1 preferentially uses PGH2 from the inducible isoform of COX (COX-2). PGs act in an autocrine and/or paracrine manner via individual families of cell surface, seven-transmembrane domain, G protein–coupled receptors. For example, PGE2 acts via a family of four EP receptors termed EP1 to EP4 (3).
- Figure 2.
The relationship between EP receptor (EP) activation by PGE2 and other signal transduction pathways. Signaling through EP2 leads to GSK-3 phosphorylation via a protein kinase A–dependent mechanism (A). EP4 receptor activation also leads to GSK-3 phosphorylation, but this occurs via a mechanism involving phosphatidylinositol 3-kinase and AKT (B). GSK-3 inactivation by EP2 and EP4 signaling in human embryonic kidney cells has been shown to lead to increased transcriptional activity of β-catenin, presumably via an increase in β-catenin protein levels, consequent on reduced β-catenin phosphorylation by GSK-3. EP4 receptor signaling also leads to ERK signaling. EP1 receptor signaling can also activate ERK signaling in human colorectal cancer cells. Whether activation of phosphatidylinositol 3-kinase and ERK signaling occurs directly from EP receptors or indirectly through a mechanism that could involve intracellular (C1) or extracellular (C2) EGFR activation is currently unknown. Abbreviations: (-), inhibition; EGR-1, early growth response factor.
- Figure 3.
PGE2-EP receptor signaling during intestinal tumorigenesis. PGE2 (derived from COX-1-mediated and/or COX-2-mediated PG synthesis pathways) can act in an autocrine and/or paracrine manner in stromal and epithelial cell compartments of tumors. It is unclear what the contribution is of each cellular compartment to PGE2 bioactivity in colorectal neoplasms. Currently, evidence is perhaps strongest for a role for stromal cell (fibroblast and/or macrophage) EP receptor (subtypes 2 and 3) signaling in promotion of angiogenesis (A) and impairment of host immune antitumor surveillance (B). PGE2 also contributes to T-lymphocyte development (87) and a switch from a Th1 to Th2 predominant immune response (88). It is unknown whether endothelial cells express EP receptors and so whether PGE2 has direct activity on the vasculature. At least part of the angiogenic activity of COX-2 is believed to be mediated by increased expression of the proangiogenic factor VEGF. Direct PGE2-EP receptor signaling (subtypes 2 and 4) in epithelial cells is also likely to be important in intestinal neoplasms in vivo (C).
Tables
- Table 1.
EP receptor signaling pathways and cellular localization in the normal large intestine
Receptor Second Messenger Signal Tissue Localization Physiologic Role in the GI Tract EP1* Phospholipase C/inositol trisphosphate Epithelium (H), epithelium,† glial cells, and longitudinal muscle (R) GI tract motility (R) EP2 Increased cAMP Epithelium† (R) Chloride secretion (H) EP3‡ Decreased cAMP Epithelium (H), epithelium,† glial cells, and longitudinal muscle (R) Duodenal bicarbonate secretion (M) and GI tract motility (R) EP4 Increased cAMP Epithelium and lamina propria cells (H), and epithelium† (M and R) Gastric mucus production (R) and chloride secretion (H) ↵* There are two human EP1 splice variants.
↵† mRNAs for all four EP receptors are strongly expressed by goblet cells in rat colonic epithelium (29).
↵‡ There are eight human EP3 splice variants; at least one of which mediates an increase in intracellular cAMP levels via Gs. Activation of at least two EP3 isoforms also leads to increased inositol trisphosphate levels via Gq.
- Table 2.
The effect of PGE2 and PGE2 analogues on rodent intestinal tumorigenesis
Model PGE2 Analogue EP Receptor Activity Weekly Dose* (μg) Duration (wk) % Untreated Tumor Number Change in Tumor Size ApcMin/+ mouse (63) dmPGE2 + 17-phenyl-trinor-PGE2 EP2–EP4 180 1† 83 ↓ EP1, EP3 180 ApcMin/+ mouse (65) dmPGE2 EP2–EP4 0.03 7 ∼50 ↓ Rat azoxymethane-induced colon carcinogenesis (64) PGE2‡ EP1–EP4 100 25 280 ↑ - Table 3.
The number of colonic ACF or intestinal polyps in mouse models of intestinal tumorigenesis following either genetic deletion or pharmacologic inhibition of EP receptor subtypes or COX isoforms
Receptor Azoxymethane-Induced ACF Development* ApcMin/+ Mouse Polyposis† ApcΔ716 Mouse Polyposis† EP1 65% (GD; ref. 70) 56% (P; ref. 70) No difference (GD; ref. 68) 65% (P; refs. 70, 71) No Δ polyp size EP2 ND ND 58% (GD; ref. 68) EP3 No difference (GD; ref. 67) ND No difference (GD; ref. 68) EP4 56% (GD; ref. 67) 69% (P; ref. 67) No difference (EP4+/− only; ref. 68) 67% (P; ref. 67) Polyp size decreased COX-1 60% (P; ref. 72) 23% (GD; ref. 5) 59%‡ (P; ref. 72) COX-2 63% (P; ref. 73) 16% (GD; ref. 5) 14% (GD; ref. 76) 3%§ (P; ref. 74) 29% (P; ref. 75) 45% (P; refs. 77, 78) Anti-PGE2 antibody ND 67% (63) ND No Δ polyp size NOTE: ND, not determined.
↵* Azoxymethane-induced ACF number following either genetic deletion (GD) or pharmacologic inhibition (P) as a percentage of wild-type or control ACF multiplicity.
↵† Polyp (or adenoma) number following either genetic deletion (GD) or pharmacologic inhibition (P) as a percentage of wild-type or control polyp multiplicity. Δ, change.
↵‡ The Apc1309 mouse model of familial adenomatous polyposis was used in this study.
↵§ Percentage of azoxymethane-induced tumor (not ACF) multiplicity in untreated rats.
Volume 3, Issue 8
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- Article
- Abstract
- The Prostaglandin Synthesis Pathway during Colorectal Carcinogenesis
- PGE2 Is the Predominant PG during Colorectal Carcinogenesis
- PGE2 Production by Human Colorectal Cancer Cells In vitro
- EP Receptors
- The Effect of PGE2 on Colorectal Epithelial Cells In vitro
- The Effect of PGE2 on Colorectal Epithelial Cell Proliferation and Intestinal Tumorigenesis In vivo
- Expression of Individual EP Receptor Isoforms in Normal Large Intestine and during Intestinal Tumorigenesis
- The Role of Individual EP Receptor Isoforms during Intestinal Tumorigenesis
- Therapeutic Implications of EP Receptor Signaling for Treatment of GI Cancer
- Summary
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- References
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