Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E2-dependent activation of type II protein kinase A

Troy Payner, H. Anne Leaver, Brian Knapp, Ian R. Whittle, Ovidiu C. Trifan, Steven Miller, Maria Teresa Rizzo

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Dysregulation of enzymes involved in prostaglandin biosynthesis plays a critical role in influencing the biological behavior and clinical outcome of several tumors. In human gliomas, overexpression of cyclooxygenase-2 has been linked to increased aggressiveness and poor prognosis. In contrast, the role of prostaglandin E synthase in influencing the biological behavior of human gliomas has not been established. We report that constitutive expression of the microsomal prostaglandin E synthase-1 (mPGES-1) is associated with increased prostaglandin E2 (PGE2) production and stimulation of growth in the human astroglioma cell line U87-MG compared with human primary astrocytes. Consistently, pharmacologic and genetic inhibition of mPGES-1 activity and expression blocked the release of PGE2 from U87-MG cells and decreased their proliferation. Conversely, exogenous PGE2 partially overcame the antiproliferative effects of mPGES-1 inhibition and stimulated U87-MG cell proliferation in the absence of mPGES-1 inhibitors. The EP2/EP4 subtype PGE2 receptors, which are linked to stimulation of adenylate cyclase, were expressed in U87-MG cells to a greater extent than in human astrocytes. PGE2 increased cyclic AMP levels and stimulated protein kinase A (PKA) activity in U87-MG cells. Treatment with a selective type II PKA inhibitor decreased PGE2-induced U87-MG cell proliferation, whereas a selective type I PKA inhibitor had no effect. Taken together, these results are consistent with the hypothesis that mPGES-1 plays a critical role in promoting astroglioma cell growth via PGE2-dependent activation of type II PKA.

Original languageEnglish (US)
Pages (from-to)1817-1826
Number of pages10
JournalMolecular cancer therapeutics
Volume5
Issue number7
DOIs
StatePublished - Jul 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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