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

Abstract

Human lung adenocarcinoma A549 cells stably transfected with TPalpha (A549-TPalpha) 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-TPalpha 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 beta-catenin/TCF/LEF pathway also participated in the induction. The activation of key signaling molecules, ERK, p38 MAPK, CREB and NF-kappaB, 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-kappaB was mediated by PKA, PKC and ERK. The role of CREB and NF-kappaB 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-kappaB sites are critical for the COX-2 induction. Distal NF-kappaB site is essential for the basal induction of the COX-2 transcription, whereas CRE and proximal NF-kappaB sites are important for the induced transcription. These results indicate that I-BOP-induced COX-2 expression through multiple signaling pathways.

• Authors: Jingyan Wei, Weili Yan, Xiuling Li, Wen-Chang Chang, Hsin-Hsiung Tai
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 74 Issue 5 Pg. 787-800 (Sep 01 2007) ISSN: 1873-2968 [Electronic] England
• PMID: 17632087 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Fatty Acids, Unsaturated
• Protein Isoforms
• Receptors, Thromboxane
• Receptors, Thromboxane A2, Prostaglandin H2
• 7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid
• Cyclooxygenase 2

Topics

• Adenocarcinoma (enzymology, genetics, metabolism)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Cyclooxygenase 2 (biosynthesis, genetics)
• Enzyme Induction (drug effects)
• Fatty Acids, Unsaturated (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (enzymology, genetics, metabolism)
• Protein Isoforms
• Receptors, Thromboxane (agonists, metabolism)
• Receptors, Thromboxane A2, Prostaglandin H2 (metabolism)
• Signal Transduction (drug effects)
• Time Factors