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Research Articles: Therapeutics

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

¹ Indianapolis Neurosurgical Group; ² Signal Transduction Laboratory, Methodist Research Institute; Departments of ³ Pharmacology and Toxicology and ⁴ Surgery, Indiana University School of Medicine, Indianapolis, Indiana; ⁵ Johnson & Johnson Pharmaceutical Research and Development LLC, Raritan, New Jersey; and ⁶ Department of Clinical Neurosciences, Edinburgh University, Edinburgh, United Kingdom

Requests for reprints: Maria Teresa Rizzo, Signal Transduction Laboratory, Methodist Research Institute, Room E504, 1800 North Capitol, Indianapolis, IN 46202. Phone: 317-962-6891; Fax: 317-962-9369. E-mail: mrizzo{at}clarian.org

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. [Mol Cancer Ther 2006;5(7):1817–26]

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Received 12/31/05; revised 3/31/06; accepted 5/ 4/06.