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, James A. Fagin

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Abstract

RET/PTC rearrangements are believed to be tumor-initiating events in papillary thyroid carcinomas. We identified microsomal prostaglandin E 2 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.

Original languageEnglish (US)
Pages (from-to)52131-52138
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number52
DOIs
StatePublished - Dec 26 2003

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Puxeddu, E., Mitsutake, N., Knauf, J. A., Moretti, S., Kim, H. W., Seta, K. A., Brockman, D., Myatt, L., Millhorn, D. E., & Fagin, J. A. (2003). 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. Journal of Biological Chemistry, 278(52), 52131-52138. https://doi.org/10.1074/jbc.M306003200