PGE2‐mediated upregulation of iNOS in murine breast cancer cells through the activation of EP4 receptors
- 28 October 2003
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 108 (3) , 384-389
- https://doi.org/10.1002/ijc.11575
Abstract
We report here that endogenous prostaglandin E2 (PGE2) resulting from cyclooxygenase (COX)‐2 expression in a highly metastatic murine breast cancer cell line C3L5 upregulates IFN‐γ + LPS‐induced nitric oxide (NO) synthase (iNOS) expression and NO production. This action of PGE2 is mediated through the EP4 receptor in a cAMP‐dependent manner. Both nonselective and selective COX‐2 inhibitors suppressed IFN‐γ + LPS‐induced NO production, which was largely restored by exogenous PGE2 or EP4 receptor agonist PGE1 alcohol. EP4 antagonist AH‐23848B inhibited NO production with a concomitant downregulation of iNOS mRNA in IFN‐γ + 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 EP4 receptor‐mediated upregulation of iNOS in COX‐2‐expressing breast cancer cells suggest that blocking COX‐2 and/or EP4 may provide a simple therapeutic modality in this tumor model.Keywords
This publication has 28 references indexed in Scilit:
- Nitric oxide‐mediated promotion of mammary tumour cell migration requires sequential activation of nitric oxide synthase, guanylate cyclase and mitogen‐activated protein kinaseInternational Journal of Cancer, 2003
- Salicylate Suppresses Macrophage Nitric-oxide Synthase-2 and Cyclo-oxygenase-2 Expression by Inhibiting CCAAT/Enhancer-binding Protein-β Binding via a Common Signaling PathwayPublished by Elsevier ,2002
- Selective Suppression of CCAAT/Enhancer-binding Protein β Binding and Cyclooxygenase-2 Promoter Activity by Sodium Salicylate in Quiescent Human FibroblastsJournal of Biological Chemistry, 2001
- Nitric oxide synthase 2 and cyclooxygenase 2 interactions in inflammationImmunologic Research, 2000
- Nitric Oxide Synthase Inhibition by NG-Nitro-l-Arginine Methyl Ester Inhibits Tumor-Induced Angiogenesis in Mammary TumorsThe American Journal of Pathology, 1999
- Interaction between nitric oxide and cyclooxygenase pathwaysProstaglandins, Leukotrienes & Essential Fatty Acids, 1996
- A novel inhibitory prostanoid receptor in piglet saphenous veinProstaglandins, 1994
- Eradication of spontaneous and experimental adenocarcinoma metastases with chronic indomethacin and intermittent IL‐2 therapyInternational Journal of Cancer, 1993
- Induction of human hsp60 expression in monocytic cell linesInternational Immunology, 1992
- Arachidonic acid release in BW755C-pretreated rat peritoneal mast cells stimulated with A23187, concanavalin A and compound 4880Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1987