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dc.contributor.authorLooby, Eileen
dc.contributor.authorAbdel-Latif, Mohamed M M
dc.contributor.authorAthié-Morales, Veronica
dc.contributor.authorDuggan, Shane
dc.contributor.authorLong, Aideen
dc.contributor.authorKelleher, Dermot
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
refterms.dateFOA2018-09-03T10:37:30Z
html.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.


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