Cancer Cell Biology

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

  1. Alexander V. Timoshenko1,
  2. Peeyush K. Lala1,
  3. Chandan Chakraborty1,2,†,*

Article first published online: 28 OCT 2003

DOI: 10.1002/ijc.11575

Issue

International Journal of Cancer

International Journal of Cancer

Volume 108, Issue 3, pages 384–389, 20 January 2004

Additional Information

How to Cite

Timoshenko, A. V., Lala, P. K. and Chakraborty, C. (2004), PGE2-mediated upregulation of iNOS in murine breast cancer cells through the activation of EP4 receptors. Int. J. Cancer, 108: 384–389. doi: 10.1002/ijc.11575

Author Information

  1. 1

    Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada

  2. 2

    Department of Pathology, University of Western Ontario, London, Ontario, Canada

  1. †

    Fax: +519-661-3370

*Department of Pathology, University of Western Ontario, London, Ontario, N6A 5C1, Canada

Publication History

  1. Issue published online: 21 NOV 2003
  2. Article first published online: 28 OCT 2003
  3. Manuscript Accepted: 26 AUG 2003
  4. Manuscript Revised: 28 JUL 2003
  5. Manuscript Received: 26 MAY 2003

Funded by

  • Canadian Breast Cancer Research Alliance. Grant Number: 012312
  • Breast Cancer Society of Canada

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Keywords:

  • cyclooxygenase;
  • cAMP;
  • EP receptors;
  • nitric oxide;
  • nitric oxide synthase;
  • prostaglandin E2

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. © 2003 Wiley-Liss, Inc.

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