Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, ERK, and NF-κB, but not p38 MAPK, pathways

Ming Shyan Chang, Bing Chang Chen, Ming Tze Yu, Joen Rong Sheu, Tseng Fu Chen, Chien Huang Lin

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97 Citations (Scopus)

Abstract

In this study, we investigated the signaling pathway involved in cyclooxygenase-2 (COX-2) expression and prostaglandin E 2 (PGE 2) release by phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, in human pulmonary epithelial cells (A549). PMA-induced COX-2 expression was attenuated by PKC inhibitors (Go 6976 and Ro 31-8220), a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), a MEK inhibitor (PD 098059), and an NF-κB inhibitor (PDTC), but not by a tyrosine kinase inhibitor (genistein) or a p38 MAPK inhibitor (SB 203580). PMA also caused the activation of Ras, Raf-1, and ERK1/2. PMA-induced activation of Ras and Raf-1 was inhibited by Ro 31-8220 and manumycin A. PMA-mediated activation of ERK1/2 was inhibited by Ro 31-8220, manumycin A, GW 5074, and PD 098059. Stimulation of cells with PMA caused IκBα phosphorylation, IκBα degradation, and the formation of a NF-κB-specific DNA-protein complex. The PMA-mediated increase in κB-luciferase activity was inhibited by Ro 31-8220, manumycin A, GW5074, PD 098059, and PDTC. Taken together, these results indicate that PMA might activate PKC to elicit activation of the Ras/Raf-1/ERK1/2 pathway, which in turn initiates NF-κB activation, and finally induces COX-2 expression and PGE 2 release in A549 cells.

Original languageEnglish
Pages (from-to)299-310
Number of pages12
JournalCellular Signalling
Volume17
Issue number3
DOIs
Publication statusPublished - Mar 2005
Externally publishedYes

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Keywords

  • A549 cells
  • Cyclooxygenase-2
  • ERK1/2
  • NF-κB
  • PKC
  • PMA
  • Raf-1
  • Ras

ASJC Scopus subject areas

  • Cell Biology

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