PT - JOURNAL ARTICLE AU - Ruyue Ji AU - Chih-Ling Chou AU - Wei Xu AU - Xiao-Bo Chen AU - David F. Woodward AU - John W. Regan TI - EP1 Prostanoid Receptor Coupling to G<sub>i/o</sub> Upregulates the Expression of Hypoxia-Inducible Factor-1α Through Activation of a Phosphoinositide-3 Kinase Signaling Pathway AID - 10.1124/mol.110.063933 DP - 2010 Jan 01 TA - Molecular Pharmacology PG - mol.110.063933 4099 - http://molpharm.aspetjournals.org/content/early/2010/03/24/mol.110.063933.short 4100 - http://molpharm.aspetjournals.org/content/early/2010/03/24/mol.110.063933.full AB - The EP1 prostanoid receptor is one of four subtypes whose cognate physiological ligand is prostaglandin-E2 (PGE2). It is in the family of G-protein coupled receptors and is known to activate Ca2+ signaling, although relatively little is known about other aspects of EP1 receptor signaling. In HEK cells expressing human EP1 receptors, we now show that PGE2 stimulation of the EP1 receptor upregulates the expression of hypoxia-inducible factor-1α (HIF-1α), which can be completely blocked by pertussis toxin, indicating coupling to Gi/o. This upregulation of HIF-1α occurs under normoxic conditions and could be inhibited with wortmannin, Akt inhibitor and rapamycin, consistent with the activation of a phosphoinositide-3 kinase/Akt/mTOR signaling pathway, respectively. In contrast to the hypoxia induced upregulation of HIF-1α, which involves decreased protein degradation, the upregulation of HIF-1α 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 hepatocellular carcinoma cells (HepG2) recapitulated the normoxic upregulation of HIF-1α observed in HEK cells, was pertussis toxin sensitive, and involved the activation of mTOR signaling and phosphorylation of rpS6. Additionally, treatment of HepG2 cells with sulprostone, an EP1 selective agonist, upregulated the mRNA expression of vascular endothelial growth factor-C, a HIF regulated gene. HIF-1α is known to promote tumour growth and metastasis and is often upregulated in cancer. Our findings provide a potential mechanism by which increased PGE2 biosynthesis could upregulate the expression of HIF-1α and promote tumorigenesis.The American Society for Pharmacology and Experimental Therapeutics