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J. Biol. Chem., Vol. 278, Issue 52, 52131-52138, December 26, 2003

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Microsomal Prostaglandin E₂ Synthase-1 Is Induced by Conditional Expression of RET/PTC in Thyroid PCCL3 Cells through the Activation of the MEK-ERK Pathway^*

Efisio Puxeddu¶, Norisato Mitsutake¶||, Jeffrey A. Knauf, Sonia Moretti, Hei W. Kim**, Karen A. Seta**, Diane Brockman, Leslie Myatt, David E. Millhorn**, and James A. Fagin

From the Division of Endocrinology and Metabolism, the ^**Department of Genome Science, and the Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 and the Dipartimento di Medicina Interna, University of Perugia, Perugia 06126, Italy

RET/PTC rearrangements are believed to be tumor-initiating events in papillary thyroid carcinomas. We identified microsomal prostaglandin E₂ synthase-1 (mPGES-1) as a RET/PTC-inducible gene through subtraction hybridization cloning and expression profiling with custom microarrays. The inducible prostaglandin E₂ (PGE₂) biosynthetic enzymes cyclooxygenase-2 (COX-2) and mPGES-1 are up-regulated in many cancers. COX-2 is overexpressed in thyroid malignancies compared with benign nodules and normal thyroid tissues. Eicosanoids may promote tumorigenesis through effects on tumor cell growth, immune surveillance, and angiogenesis. Conditional RET/PTC1 or RET/PTC3 expression in PCCL3 thyroid cells markedly induced mPGES-1 and COX-2. PGE₂ was the principal prostanoid and up-regulated (by 60-fold), whereas hydroxyeicosatetraenoic acid metabolites were decreased, consistent with shunting of prostanoid biosynthesis toward PGE₂ by coactivation of the two enzymes. RET/PTC activated mPGES-1 gene transcription. Based on experiments with kinase inhibitors, with PCCL3 cell lines with doxycycline-inducible expression of RET/PTC mutants with substitutions of critical tyrosine residues in the kinase domain, and lines with inducible expression of activated mutants of H-RAS and MEK1, RET/PTC was found to regulate mPGES-1 through Shc-RAS-MEK-ERK. These data show a direct relationship between activation of a tyrosine kinase receptor oncogene and regulation of PGE₂ biosynthesis. As enzymes involved in prostanoid biosynthesis can be targeted with pharmacological inhibitors, these findings may have therapeutic implications.

Received for publication, June 6, 2003 , and in revised form, October 6, 2003.

^* This work was supported in part by National Institutes of Health Grant CA50706 (to J. A. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Both authors contributed equally to this work.

^|| Supported in part by the Nakayama Foundation for Human Science and Sumitomo Life Social Welfare Services Foundation.

To whom correspondence should be addressed: Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, P. O. Box 670547, Cincinnati, OH 45267-0547. Tel.: 513-558-4444; Fax: 513-558-8581; E-mail: james.fagin{at}uc.edu.

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