EP1 Prostanoid Receptor Coupling to G_i/oUp-Regulates the Expression of Hypoxia-Inducible Factor-1α through Activation of a Phosphoinositide-3 Kinase Signaling Pathway

Abstract

The EP1 prostanoid receptor is one of four subtypes whose cognate physiological ligand is prostaglandin-E2 (PGE 2 ). It is in the family of G-protein-coupled receptors and is known to activate Ca 2ϩ signaling, although relatively little is known about other aspects of E-type prostanoid receptor (EP) 1 receptor signaling. In human embryonic kidney (HEK) cells expressing human EP1 receptors, we now show that PGE 2 stimulation of the EP1 receptor up-regulates the expression of hypoxia-inducible factor-1␣ (HIF-1␣), which can be completely blocked by pertussis toxin, indicating coupling to G i/o . This up-regulation of HIF-1␣ occurs under normoxic conditions and could be inhibited with wortmannin, Akt inhibitor, and rapamycin, consistent with the activation of a phosphoinositide-3 kinase/Akt/ mammalian target of rapamycin (mTOR) signaling pathway, respectively. In contrast to the hypoxia-induced up-regulation of HIF-1␣, which involves decreased protein degradation, the up-regulation of HIF-1␣ by the EP1 receptor was associated with the phosphorylation of ribosomal protein S6 (rpS6), suggesting activation of the ribosomal S6 kinases and increased translation. Stimulation of endogenous EP1 receptors in human HepG2 hepatocellular carcinoma cells recapitulated the normoxic up-regulation of HIF-1␣ observed in HEK cells, was sensitive to pertussis toxin, and involved the activation of mTOR signaling and phosphorylation of rpS6. In addition, treatment of HepG2 cells with sulprostone, an EP1-selective agonist, up-regulated the mRNA expression of vascular endothelial growth factor-C, a HIF-regulated gene. HIF-1␣ is known to promote tumor growth and metastasis and is often up-regulated in cancer. Our findings provide a potential mechanism by which increased PGE 2 biosynthesis could up-regulate the expression of HIF-1␣ and promote tumorigenesis. E-type prostanoid receptors (EP) are the receptors that mediate the actions of prostaglandin E 2 (PGE 2 ) and are members of the superfamily of G-protein coupled receptors.There are four primary subtypes of EP receptors, named EP1, EP2, EP3, and EP4. The EP1, EP2, and EP3 receptors were initially classified on the basis of their pharmacology and upon differences in their functional effects on various types of smooth muscle, as well as their activation of second-messenger signaling pathways (Coleman et al., 1994). Thus, PGE 2 stimulation of EP1 receptors produced contractile responses that could be selectively blocked with 8-chloro-dibenz [b,f][1,4]oxazepine-10(11H)-carboxy-(2-acetyl)hydrazide (SC-19220) and were involved in the mobilization of intracellular Ca 2ϩ . PGE 2 stimulation of EP2

IL-1β-Mediated Repression of microRNA-101 Is Crucial for Inflammation-Promoted Lung Tumorigenesis

“…It has been previously shown that IL-1b activates HIF1a through the NF-kB-COX2 pathway (34,35). We thus examined whether COX2 is required for the IL1b/HIF1a-mediated repression of mir-101 in NSCLC cells.…”

Dihydrotestosterone attenuates hypoxia inducible factor-1α and cyclooxygenase-2 in cerebral arteries during hypoxia or hypoxia with glucose deprivation

“…Aside from being a transcription factor in the pathway leading to increased COX-2 levels, HIF-1␣ also participates in considerable cross-talk with the COX-2 pathway. For example, under normoxia the COX-2 end product PGE 2 activates its EP1 receptor to increase HIF-1␣ levels in human embryonic kidney cells (18). During hypoxia, HIF-1␣ binds to the Toll-like receptor 4 promoter causing upregulation of Toll-like receptor 4.…”

Regulation of Calcium Channels and Exocytosis in Mouse Adrenal Chromaffin Cells by Prostaglandin EP3 Receptors

“…The data presented above demonstrate that PGE 2 acts through a G i/o -coupled GPCR to inhibit I Ca in mouse chromaffin cells. Of the four known receptors for PGE 2 , termed EP1 to EP4, only EP3 typically couples to G i/o -type G proteins, although it has been reported that EP1 receptors might also couple to G i/o at least in some cell types (Ji et al, 2010). Both EP3 and EP1 receptors have been reported previously in the adrenal medulla (Breyer et al, 1993;Namba et al, 1993;Engström et al, 2008). ]…”