Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells.
Authors
Looby, EileenAbdel-Latif, Mohamed M M
Athié-Morales, Veronica
Duggan, Shane
Long, Aideen
Kelleher, Dermot
Affiliation
Department of Clinical Medicine and Institute of Molecular Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland. loobye@tcd.ieIssue Date
2009MeSH
AdenocarcinomaApoptosis
Barrett Esophagus
Cell Growth Processes
Cell Line, Tumor
Collagen Type XI
Cyclooxygenase 2
DNA, Neoplasm
Deoxycholic Acid
Enzyme Induction
Esophageal Neoplasms
Humans
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases
Proto-Oncogene Proteins c-fos
Proto-Oncogene Proteins c-jun
Signal Transduction
Transcription Factor AP-1
p38 Mitogen-Activated Protein Kinases
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Show full item recordCitation
Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells. 2009, 9:190 BMC CancerJournal
BMC cancerDOI
10.1186/1471-2407-9-190PubMed ID
19534809Abstract
BACKGROUND: The progression from Barrett's metaplasia to adenocarcinoma is associated with the acquirement of an apoptosis-resistant phenotype. The bile acid deoxycholate (DCA) has been proposed to play an important role in the development of esophageal adenocarcinoma, but the precise molecular mechanisms remain undefined. The aim of this study was to investigate DCA-stimulated COX-2 signaling pathways and their possible contribution to deregulated cell survival and apoptosis in esophageal adenocarcinoma cells. METHODS: Following exposure of SKGT-4 cells to DCA, protein levels of COX-2, MAPK and PARP were examined by immunoblotting. AP-1 activity was assessed by mobility shift assay. DCA-induced toxicity was assessed by DNA fragmentation and MTT assay. RESULTS: DCA induced persistent activation of the AP-1 transcription factor with Fra-1 and JunB identified as the predominant components of the DCA-induced AP-1 complex. DCA activated Fra-1 via the Erk1/2- and p38 MAPK while Erk1/2 is upstream of JunB. Moreover, DCA stimulation mediated inhibition of proliferation with concomitant low levels of caspase-3-dependent PARP cleavage and DNA fragmentation. Induction of the anti-apoptotic protein COX-2 by DCA, via MAPK/AP-1 pathway appeared to balance the DCA mediated activation of pro-apoptotic markers such as PARP cleavage and DNA fragmentation. Both of these markers were increased upon COX-2 suppression by aspirin pretreatment prior to DCA exposure. CONCLUSION: DCA regulates both apoptosis and COX-2-regulated cell survival in esophageal cells suggesting that the balance between these two opposing signals may determine the transformation potential of DCA as a component of the refluxate.Language
enISSN
1471-2407ae974a485f413a2113503eed53cd6c53
10.1186/1471-2407-9-190
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