EP1 prostaoid receptor mediated upregulation of hypoxia inducible factor‐1α (HIF‐1α) under normoxic conditions by activation of Gi‐coupled phosphoinositide 3‐kinase (PI3K) signaling

Abstract

The EP1 prostanoid receptor is one of four receptor subtypes activated by prostaglandin‐E2 (PGE2) and is known to couple to Gq to activate calcium signaling. Recently we have found that PGE2 stimulation of the human EP1 receptor can upregulate the expression of HIF‐1α under normoxic conditions. HIF‐1 is a heterodimeric transcription factor consisting of HIF‐1α and HIF‐1β. While HIF‐1β is expressed constitutively, HIF‐1α expression is typically regulated by hypoxia. Thus, during normoxia HIF‐1α is rapidly degraded, whereas, during hypoxia its degradation is inhibited: HIF‐1α then accumulates, combining with HIF‐1β to activate transcription via binding to hypoxia response elements (HRE) in HIF‐regulated target genes. We have found by Western blot analysis that the upregulation of HIF‐1α by PGE2 stimulation of the human EP1 receptor expressed in HEK cells is completely blocked by pretreatment of cells with pertussis toxin, an inhibitor of Gi/o. Functional activation of an HRE/luciferase reporter gene is also blocked by this treatment. Furthermore, pretreatment of cells with wortmannin, an inhibitor of PI3K, or with Akt‐inhibitor, decreases the PGE2 stimulated upregulation of HIF‐1α protein expression and HRE functional activity. In conclusion PGE2 stimulation of the EP1 receptor can upregulate the expression of HIF‐1α by a mechanism involving coupling of the receptor to Gi and activation of PI3K and Akt signaling.