Hence as both molecules are constitutively selleck chemicals Ponatinib expressed in SKGT4 cells, the enhanced levels of JunB induced by DCA might poten tially have a negative effect on c Jun DNA binding. Fos and Jun proteins can heterodimerise while only the mem bers of the Jun family are capable of homodimerisation. Fos Jun heterodimers are more stable than Jun homodim ers. Therefore, our data suggest that a Fra 1 JunB het erodimer is the DCA induced AP 1 complex. In these circumstances, this complex could act as a growth pro moter in response to DCA in esophageal cells. Bile acids can exert their tumor promoting activity by affecting intracellular signaling pathways, which alters proliferation and apoptosis. MAPKs constitute an impor tant group of signaling mediators that govern cellular processes such as proliferation and cell death.

DCA pro motes cell survival through the induction of MAPKs in pri mary hepatocytes and colonic cells. The present study demonstrated that DCA activated the MAPKs Erk1 2 and p38, but it is unable to regulate JNK activation. COX 2 expression can also be regulated by MAPKs both directly by mRNA stabilization as shown in intestinal epi thelial cells and monocytes and indirectly through activation of AP 1 complexes. Here we used specific pharmacological inhibitors of the MAPK cascades to identify the pathways mediating DCA induced COX 2 expression in SKGT4 cells. COX 2 expression was com pletely blocked by the PD98059 and SB203580 com pounds demonstrating the involvement of Raf Mek1 2 Erk1 2 and MMK3 6 p38 pathways in DCA induced COX 2 expression.

COX 2 may be specifically important in esophageal carcinogenesis, as COX 2 expression is fre quently upregulated in Barretts esophagus, esophageal cancer and in animal models of reflux. The specificity of pharmacological inhibitors should be con sidered, because many of these inhibitors block various signal transduction proteins. However, MAPKs inhibitors such as PD98059 and SB203580 are well established spe cific inhibitors of ERK and p38 pathway, respectively, and have been tested in many systems for their specificity in inhibiting MAPKs activity. In vitro, prolonged exposure of colonic cells to DCA induced apoptosis and caused morphological changes that were characteristic of apoptosis, however, apop tosis resistant clones may be selected after frequent expo sure to the cytotoxic bile DCA.

In vivo, bile acid induced apoptosis has been linked with compensatory proliferation of crypt epithelial cells. Rates of apopto sis have been demonstrated Batimastat to be low in Barretts epithe lium, potentially contributing to the malignant process. While DCA induced low levels of apoptosis in this study, the effects on cell survival appear to have been balanced at least partially through DCA induced COX 2. Specifically DCA induced PARP cleavage was enhanced by COX inhibition.