Activation of thromboxane receptor α induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells

Jingyan Wei, Weili Yan, Xiuling Li, Wen Chang Chang, Hsin Hsiung Tai

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25 Citations (Scopus)

Abstract

Human lung adenocarcinoma A549 cells stably transfected with TPα (A549-TPα) were used to study agonist I-BOP-induced expression of cyclooxygenase-2 (COX-2) and the related mechanisms of induced expression. I-BOP, a TP agonist, induced a time- and dose-dependent expression of COX-2 in A549-TPα cells. The signaling pathways of I-BOP-induced COX-2 expression were elucidated by using various inhibitors of the signaling molecules. The effects of these inhibitors were assessed at protein level, enzyme activity and promoter activity of COX-2. Within MAPK family, both ERK and p38 MAPK but not JNK/SAPK pathways were involved in the induction. Other pathways such as JAK/Stat3 pathway and β-catenin/TCF/LEF pathway also participated in the induction. The activation of key signaling molecules, ERK, p38 MAPK, CREB and NF-κB, involved in the COX-2 transcription was further studied at the phosphorylation step. Activation of ERK and p38 MAPK appeared to be mediated primarily by transactivation of EGFR, whereas activation of CREB and NF-κB was mediated by PKA, PKC and ERK. The role of CREB and NF-κB in I-BOP-induced COX-2 expression was further explored at the promoter level. Studies on promoter fragments and mutation of responsive motifs indicated that CRE and NF-κB sites are critical for the COX-2 induction. Distal NF-κB site is essential for the basal induction of the COX-2 transcription, whereas CRE and proximal NF-κB sites are important for the induced transcription. These results indicate that I-BOP-induced COX-2 expression through multiple signaling pathways.

Original languageEnglish
Pages (from-to)787-800
Number of pages14
JournalBiochemical Pharmacology
Volume74
Issue number5
DOIs
Publication statusPublished - Sep 1 2007
Externally publishedYes

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Keywords

  • Cyclooxygenase-2
  • Gene expression
  • Prostaglandins
  • Signal transduction
  • Thromboxane receptor

ASJC Scopus subject areas

  • Pharmacology

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