BILE ACID INDUCED AP1 SIGNALING IN COLON CANCER

申请人描述：该项目的总体目标是

APPLICANT'S DESCRIPTION: The overall objective of this project is to delineate the mechanism through which bile acids alter colon tumor etiology by examining the effect that bile acid-mediated changes in signal transduction and gene expression have on cell fate. Deoxycholic acid (DCA) can stimulate gene expression by activating the AP-1 transcription factor through up regulation of the ras/erk pathway, suggesting that DCA acts as a tumor promoter by aberrantly up regulating protooncogene activity and mimicking the effects of gene mutations. Interestingly, DCA also stimulates a separate protein kinase C-dependent pathway that may also cause up regulation of AP-1 through GSK-3 in the Wnt-1 signaling pathway. Interestingly, ursodeoxycholic acid (UDCA), a bile acid with chemopreventative properties, does not stimulate AP-1 activity. Instead, UDCA stimulated signaling cooperates with activated AP-1 and/or PKC signaling to induce apoptosis. Importantly, we have determined that AP-1 may be up-regulated in Min(+) mouse tumors and in the flat mucosa of AOM treated mice long after final exposure to this carcinogen, suggesting that AP-1 is aberrantly activated in vivo under conditions that foster tumor development. Consequently, we hypothesize that bile acids modulate colon cancer etiology by altering signal transduction that leads to activation of AP-1. Furthermore, we speculate that UDCA may function as a chemopreventive agent by selectively inducing apoptosis in cells where AP-1 and/or PKC is aberrantly stimulated. We will test this by: 1) determining whether DCA can modify the activity of and/or dysregulate Wnt-1 signaling, 2) examine the effect of germline mutations in the APC gene on tumor promotion/chemopreven-tion by bile, 3) characterize UDCA-mediated signaling activity in colon-derived cell lines, 4) determine whether UDCA can induce apoptosis in colonic epithelial cells with aberrant AP-1 activity, 5) Examine the effect that a diet supplemented with UDCA has on signal transduction and gene expression in the colonic epithelium of human subjects.