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.
Copyright 2003 Wiley-Liss, Inc.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cyclic AMP / pharmacology
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprostone / physiology*
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Enzyme Induction
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Enzyme Inhibitors / pharmacology
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Female
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Gene Expression Regulation, Enzymologic
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Humans
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Interferon-gamma / pharmacology
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Isoenzymes / metabolism
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Lipopolysaccharides / pharmacology
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Mammary Neoplasms, Experimental / enzymology*
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Mammary Neoplasms, Experimental / pathology
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Membrane Proteins
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Mice
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Mice, Inbred C3H
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Nitric Oxide / metabolism
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism*
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Nitric Oxide Synthase Type II
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Prostaglandin-Endoperoxide Synthases / metabolism
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Prostaglandins E / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Prostaglandin E / agonists
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Receptors, Prostaglandin E / antagonists & inhibitors
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Receptors, Prostaglandin E / metabolism*
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Receptors, Prostaglandin E, EP4 Subtype
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Tumor Cells, Cultured
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Up-Regulation
Substances
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Enzyme Inhibitors
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Isoenzymes
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Lipopolysaccharides
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Membrane Proteins
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PTGER4 protein, human
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Prostaglandins E
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Ptger4 protein, mouse
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RNA, Messenger
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP4 Subtype
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Nitric Oxide
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Interferon-gamma
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Cyclic AMP
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Dinoprostone