Up-regulation of cyclooxygenase-2 expression and prostaglandin synthesis in endometrial stromal cells by malignant endometrial epithelial cells. A paracrine effect mediated by prostaglandin E2 and nuclear factor-κB

Mitsutoshi Tamura, Siby Sebastian, Sijun Yang, Bilgin Gurates, Karen Ferrer, Hironobu Sasano, Kunihiro Okamura, Serdar E. Bulun

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64 Citations (Scopus)

Abstract

We investigated the regulation of prostaglandin production in normal endometrial stromal cells (ESC) by malignant endometrial epithelial cells. We found that cyclooxygenase (COX)-2 mRNA and protein levels and prostaglandin (PG)E2 production in ESC were significantly increased by Ishikawa malignant endometrial epithelial cell conditioned medium (MECM). By using transient transfection assays, we found that the -360/ -218-bp region of the COX-2 promoter gene was critical for MECM induction of promoter activity. This MECM-responsive region contained a variant nuclear factor (NF)-κB site at -222 to -213 that, when mutated, completely abolished COX-2 promoter activation by MECM. Employing electrophoretic mobility shift assays, we further demonstrated that binding of NF-κB p65 to this NF-κB-binding site is, in part, responsible for the COX-2 promoter activation by MECM. To investigate further the potential effects of MECM on COX-2 mRNA stability, ESC were treated with MECM in the absence or presence of actinomycin D, a general transcription inhibitor. We found that MECM significantly increased COX-2 mRNA stability. Intriguingly, we found that PGE2 was one of the major factors in MECM, which was responsible for up-regulating COX-2 expression in ESC. ECC-1 and HEC-1A malignant endometrial epithelial cell lines also produced significantly increased quantities of PGE2. In conclusion, malignant endometrial epithelial cells secrete PGE2 that induces COX-2 expression in normal endometrial stromal cells in a paracrine fashion through activation of transcription and stabilization of COX-2 mRNA.

Original languageEnglish
Pages (from-to)26208-26216
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number29
DOIs
Publication statusPublished - 2002 Jul 19

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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