PGE2-mediated upregulation of iNOS in murine breast cancer cells through the activation of EP4 receptors

Int J Cancer. 2004 Jan 20;108(3):384-9. doi: 10.1002/ijc.11575.

Abstract

We report here that endogenous prostaglandin E(2) (PGE(2)) resulting from cyclooxygenase (COX)-2 expression in a highly metastatic murine breast cancer cell line C3L5 upregulates IFN-gamma + LPS-induced nitric oxide (NO) synthase (iNOS) expression and NO production. This action of PGE(2) is mediated through the EP(4) receptor in a cAMP-dependent manner. Both nonselective and selective COX-2 inhibitors suppressed IFN-gamma + LPS-induced NO production, which was largely restored by exogenous PGE(2) or EP(4) receptor agonist PGE(1) alcohol. EP(4) antagonist AH-23848B inhibited NO production with a concomitant downregulation of iNOS mRNA in IFN-gamma + LPS-stimulated cells. cAMP dependence of NO production by cells under inducible conditions was demonstrated by the use of known modulators of intracellular cAMP. Since both COX-2 and iNOS are implicated in breast cancer progression, our findings of EP(4) receptor-mediated upregulation of iNOS in COX-2-expressing breast cancer cells suggest that blocking COX-2 and/or EP(4) may provide a simple therapeutic modality in this tumor model.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP / pharmacology
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Dinoprostone / physiology*
  • Enzyme Induction
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Interferon-gamma / pharmacology
  • Isoenzymes / metabolism
  • Lipopolysaccharides / pharmacology
  • Mammary Neoplasms, Experimental / enzymology*
  • Mammary Neoplasms, Experimental / pathology
  • Membrane Proteins
  • Mice
  • Mice, Inbred C3H
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Prostaglandins E / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Prostaglandin E / agonists
  • Receptors, Prostaglandin E / antagonists & inhibitors
  • Receptors, Prostaglandin E / metabolism*
  • Receptors, Prostaglandin E, EP4 Subtype
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Enzyme Inhibitors
  • Isoenzymes
  • Lipopolysaccharides
  • Membrane Proteins
  • PTGER4 protein, human
  • Prostaglandins E
  • Ptger4 protein, mouse
  • RNA, Messenger
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP4 Subtype
  • Nitric Oxide
  • Interferon-gamma
  • Cyclic AMP
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone