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PGE 2 ‐mediated upregulation of iNOS in murine breast cancer cells through the activation of EP 4 receptors
Author(s) -
Timoshenko Alexander V.,
Lala Peeyush K.,
Chakraborty Chandan
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.11575
Subject(s) - downregulation and upregulation , receptor , cancer research , breast cancer , cancer , chemistry , medicine , endocrinology , biology , pathology , biochemistry , gene
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‐γ + 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‐γ + 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‐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 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. © 2003 Wiley‐Liss, Inc.