Institutions | About Us | Help | Gaeilge
rian logo


Mark
Go Back
Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells
DUGGAN, SHANE; KELLEHER, DERMOT P; LONG, AIDEEN
peer-reviewed 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.
Keyword(s): Clinical Medicine
Publication Date:
2009
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Institution: Trinity College Dublin
Funder(s): Health Research Board; Higher Education Authority
Citation(s): Looby E, Abdel-Latif MM, Athie-Morales V, Duggan S, Long A, Kelleher D. 'Deoxycholate induces COX-2 expression via Erk1/2 - p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells' BMC Cancer, (9), 190, 2009
Publisher(s): BioMed Central
File Format(s): application/pdf
First Indexed: 2014-05-13 05:35:32 Last Updated: 2015-04-10 05:22:29