Abstract
BackgroundThe 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.MethodsFollowing 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.ResultsDCA 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.ConclusionDCA 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.
Highlights
The progression from Barrett's metaplasia to adenocarcinoma is associated with the acquirement of an apoptosis-resistant phenotype
We examined the possible link between DCA, AP-1 in esophageal adenocarcinoma SKGT4 cells, a cell line derived from a well-differentiated adenocarcinoma arising in Barrett's epithelium of the distal esophagus [34]
We have demonstrated a similar profile of AP-1 activation in another esophageal adenocarcinoma line OE-33
Summary
The progression from Barrett's metaplasia to adenocarcinoma is associated with the acquirement of an apoptosis-resistant phenotype. BMC Cancer 2009, 9:190 http://www.biomedcentral.com/1471-2407/9/190 turn determines the production levels of secondary bile acids [4,5,6,7]. While bile acids such as DCA cannot induce tumors, they are generally believed to be tumor promoters. Bile acids are known mediators of cellular stress [9] and have been proposed to induce apoptosis resulting in compensatory hyperproliferation, allowing for selection of apoptosis-resistant cells [10,11]. Bile acids are known to induce survival mechanisms in parallel with apoptotic pathways in hepatocytes and colonic cells [12,13]
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