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(2+) 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 alpha (HIF-1 alpha), which can be completely blocked by
pertussis toxin, indicating coupling to G(i/o). This up-regulation of HIF-1 alpha 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 alpha, which involves decreased protein degradation, the up-regulation of HIF-1 alpha 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 alpha 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 alpha 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 alpha and promote
tumorigenesis.