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

<p>Abstract</p> <p>Background</p> <p>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...

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Main Authors: Long Aideen, Duggan Shane, Athié-Morales Veronica, Abdel-Latif Mohamed MM, Looby Eileen, Kelleher Dermot
Format: Article
Language:English
Published: BMC 2009-06-01
Series:BMC Cancer
Online Access:http://www.biomedcentral.com/1471-2407/9/190
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author Long Aideen
Duggan Shane
Athié-Morales Veronica
Abdel-Latif Mohamed MM
Looby Eileen
Kelleher Dermot
author_facet Long Aideen
Duggan Shane
Athié-Morales Veronica
Abdel-Latif Mohamed MM
Looby Eileen
Kelleher Dermot
author_sort Long Aideen
collection DOAJ
description <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p>
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spelling doaj.art-01edc458d46e47158954ca021b66a5f62022-12-21T21:05:06ZengBMCBMC Cancer1471-24072009-06-019119010.1186/1471-2407-9-190Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cellsLong AideenDuggan ShaneAthié-Morales VeronicaAbdel-Latif Mohamed MMLooby EileenKelleher Dermot<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p>http://www.biomedcentral.com/1471-2407/9/190
spellingShingle Long Aideen
Duggan Shane
Athié-Morales Veronica
Abdel-Latif Mohamed MM
Looby Eileen
Kelleher Dermot
Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells
BMC Cancer
title Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells
title_full Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells
title_fullStr Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells
title_full_unstemmed Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells
title_short Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells
title_sort deoxycholate induces cox 2 expression via erk1 2 p38 mapk and ap 1 dependent mechanisms in esophageal cancer cells
url http://www.biomedcentral.com/1471-2407/9/190
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