Induction of cyclooxygenase-2 expression by prostaglandin E2 stimulation of the prostanoid EP4 receptor via coupling to Gαi and transactivation of the epidermal growth factor receptor in HCA-7 human colon cancer cells

Kenji Yoshida, Hiromichi Fujino, Sho Otake, Naofumi Seira, John W. Regan, Toshihiko Murayama

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Increased expressions of cyclooxygenase-2 (COX-2) and its downstream metabolite, prostaglandin E2 (PGE2), are well documented events in the development of colorectal cancer. Interestingly, PGE2 itself can induce the expression of COX-2 thereby creating the potential for positive feedback. Although evidence for such a positive feedback has been previously described, the specific E-type prostanoid (EP) receptor subtype that mediates this response, as well as the relevant signaling pathways, remain unclear. We now report that the PGE2 stimulated induction of COX-2 expression in human colon cancer HCA-7 cells is mediated by activation of the prostanoid EP4 receptor subtype and is followed by coupling of the receptor to Gαi and the activation of phosphatidylinositol 3-kinase. Subsequent activation of metalloproteinases releases membrane bound heparin-binding epidermal growth factor-like growth factor resulting in the transactivation of epidermal growth factor receptors and the activation of the extracellular signal-regulated kinases and induction of COX-2 expression. This induction of COX-2 expression by PGE2 stimulation of the prostanoid EP4 receptor may underlie the upregulation of COX-2 during colorectal cancer and appears to be an early event in the process of tumorigenesis.

Original languageEnglish (US)
Pages (from-to)408-417
Number of pages10
JournalEuropean Journal of Pharmacology
Volume718
Issue number1-3
DOIs
StatePublished - Sep 2 2013

Keywords

  • Colon cancer
  • Cyclooxygenase-2
  • G
  • Human prostanoid EP4 receptor
  • PGE
  • Phosphatidylinositol 3-kinase
  • Prostaglandin E

ASJC Scopus subject areas

  • Pharmacology

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