Prostaglandin E₂ upregulates EGF‐stimulated signaling in mitogenic pathways involving Akt and ERK in hepatocytes

Abstract

Prostaglandins (PGs) such as PGE2 enhance proliferation in many cells, apparently through several distinct mechanisms, including transactivation of the epidermal growth factor (EGF) receptor (EGFR) as well as EGFR-independent pathways. In this study we found that in primary cultures of rat hepatocytes PGE2 did not induce phosphorylation of the EGFR, and the EGFR tyrosine kinase blockers gefitinib and AG1478 did not affect PGE2-stimulated phosphorylation of ERK1/2. In contrast, PGE2 elicited EGFR phosphorylation and EGFR tyrosine kinase inhibitor-sensitive ERK phosphorylation in MH1C1 hepatoma cells. These findings suggest that PGE2 elicits EGFR transactivation in MH1C1 cells but not in hepatocytes. Treatment of the hepatocytes with PGE2 at 3 h after plating amplified the stimulatory effect on DNA synthesis of EGF administered at 24 h and advanced and augmented the cyclin D1 expression in response to EGF in hepatocytes. The pretreatment of the hepatocytes with PGE2 resulted in an increase in the magnitude of EGF-stimulated Akt phosphorylation and ERK1/2 phosphorylation and kinase activity, including an extended duration of the responses, particularly of ERK, to EGF in PGE2-treated cells. Pertussis toxin abolished the ability of PGE2 to enhance the Akt and ERK responses to EGF. The results suggest that in hepatocytes, unlike MH1C1 hepatoma cells, PGE2 does not transactivate the EGFR, but instead acts in synergism with EGF by modulating mitogenic mechanisms downstream of the EGFR. These effects seem to be at least in part G(i) protein-mediated and include upregulation of signaling in the PI3K/Akt and the Ras/ERK pathways.

Prostaglandins Enhance Epidermal Growth Factor-Induced DNA Synthesis in Hepatocytes by Stimulation of E Prostanoid 3 and F Prostanoid Receptors

“…This is in agreement with our previous observation that cAMP does not mediate the proliferative effects of prostaglandins in the hepatocytes (Refsnes et al, 1995). Furthermore, although EP4 receptors have been found to stimulate cyclin D1 expression and phosphorylation of EGF receptor and extracellular signal-regulated kinase in murine hepatocytes (Kataoka et al, 2005), prostaglandins do not transactivate the EGF receptor in rat hepatocytes (Nilssen et al, 2004) but act to enhance subsequent stimulation of extracellular signal-regulated kinase and Akt by EGF (Dajani et al, 2007). In addition, we found no additive effects between sulprostone and misoprostol on DNA synthesis, suggesting lack of involvement of EP4 receptors.…”

The Prostaglandin E2 Receptor, EP2, Stimulates Keratinocyte Proliferation in Mouse Skin by G Protein-dependent and β-Arrestin1-dependent Signaling Pathways

“…EGFR is a multifunctional tyrosine kinase receptor with the ability to active multiple effectors and downstream signaling pathways (48,49). In the current study, we observed that EP2 agonist-mediated transactivation of EGFR resulted in the activation of the downstream signaling effectors: ERK1/2, Akt, and STAT3.…”

“…ERK1/2 and Akt are known to be activated in cultured cells by PGE 2 (20,48,50) and to play important roles in cell proliferation and skin tumor formation (33,36). Several reports indicated that PGE 2 -stimulated ERK1/2 and Akt activation were mediated by both activated EGFR and activated PKA (20,48,51) and that both effectors contributed to keratinocyte replication and survival (33,35). However, in the present studies, Akt activation was suppressed by EGFR inhibition but not by inhibition of PKA (Figs.…”

Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats

“…From a more generalized view, prostaglandins may act to potentiate the action of growth factor signals. In an analogous model, PGE 2 may augment the action of platelet-derived growth factor; PGE 2 has low mitotic activity on its own but augments the platelet-derived growth factor signal to increase cell growth (11). Thus, some prostaglandins may act to modulate trophic signals, providing another level of regulation for key signaling pathways.…”