Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells.

Hdl Handle:
http://hdl.handle.net/10147/94168
Title:
Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells.
Authors:
Looby, Eileen; Abdel-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.ie
Citation:
Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells. 2009, 9:190 BMC Cancer
Journal:
BMC cancer
Issue Date:
2009
URI:
http://hdl.handle.net/10147/94168
DOI:
10.1186/1471-2407-9-190
PubMed ID:
19534809
Abstract:
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:
en
MeSH:
Adenocarcinoma; Apoptosis; 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
ISSN:
1471-2407

Full metadata record

DC FieldValue Language
dc.contributor.authorLooby, Eileenen
dc.contributor.authorAbdel-Latif, Mohamed M Men
dc.contributor.authorAthié-Morales, Veronicaen
dc.contributor.authorDuggan, Shaneen
dc.contributor.authorLong, Aideenen
dc.contributor.authorKelleher, Dermoten
dc.date.accessioned2010-03-12T15:33:41Z-
dc.date.available2010-03-12T15:33:41Z-
dc.date.issued2009-
dc.identifier.citationDeoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells. 2009, 9:190 BMC Canceren
dc.identifier.issn1471-2407-
dc.identifier.pmid19534809-
dc.identifier.doi10.1186/1471-2407-9-190-
dc.identifier.urihttp://hdl.handle.net/10147/94168-
dc.description.abstractBACKGROUND: 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.-
dc.language.isoenen
dc.subject.meshAdenocarcinoma-
dc.subject.meshApoptosis-
dc.subject.meshBarrett Esophagus-
dc.subject.meshCell Growth Processes-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCollagen Type XI-
dc.subject.meshCyclooxygenase 2-
dc.subject.meshDNA, Neoplasm-
dc.subject.meshDeoxycholic Acid-
dc.subject.meshEnzyme Induction-
dc.subject.meshEsophageal Neoplasms-
dc.subject.meshHumans-
dc.subject.meshMitogen-Activated Protein Kinase 1-
dc.subject.meshMitogen-Activated Protein Kinase 3-
dc.subject.meshMitogen-Activated Protein Kinases-
dc.subject.meshProto-Oncogene Proteins c-fos-
dc.subject.meshProto-Oncogene Proteins c-jun-
dc.subject.meshSignal Transduction-
dc.subject.meshTranscription Factor AP-1-
dc.subject.meshp38 Mitogen-Activated Protein Kinases-
dc.titleDeoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells.en
dc.contributor.departmentDepartment 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.ieen
dc.identifier.journalBMC canceren
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