Increased c-fos mRNA and binding to the AP-1 recognition sequence accompanies the proliferative response to deoxycholate of HT29 cells

Abstract

To further understand the molecular mechanisms of bile acid-mediated colon tumor promotion, we have examined the possible role of AP-1 activity in this process. The AP-1 complex has been reported to play an important role in control of cell growth. Our studies show that lithocholate, deoxycholate and ursodeoxycholate exhibited marked proliferative effects on a human adenocarcinoma cell line (HT29), while cholate was without effect. The proliferative effects appeared to be confined to narrow concentration windows which differed for the different bile acids. We demonstrate that deoxycholate caused an increase in expression of c-fos mRNA and increased binding to the AP-1 site, effects which were maximum at the concentration at which the bile acid induced the maximum proliferative effect on the cells. Cholate was without effect on AP-1 binding activity. In addition, we show that the AP-1 complex induced by treatment of the cells with the bile acid contained the c-fos protein. This could suggest that prolonged deregulated expression of AP-1 activity in colonic cells by certain bile acids may contribute to tumor promotion in the colon.

Genotoxic activity in human faecal water and the role of bile acids: a study using the alkaline comet assay

“…Bile acids have previously been shown to induce single-strand breaks in isolated nuclei (34) and the present study has shown the presence of DNA strand breaks and base oxidations at high bile acid concentrations; concentrations that may be reached in patients with colon cancer-associated pathology, but are unlikely to be responsible for the DNA damaging effects seen in the faecal water samples from the present study. Bile acids can also alter colonic cell proliferation (35)(36)(37), and the predominant bile acids, in both un-conjugated and conjugated forms can produce DNA adducts in vitro (38). Our observation of the much reduced genotoxicity by the sodium salt of DCA when compared to the free acid was surprising, but could be due different rates of uptake through the cell membrane.…”

Resistance to ursodeoxycholic acid-induced growth arrest can also result in resistance to deoxycholic acid-induced apoptosis and increased tumorgenicity

“…The mechanism through which bile acids bring about there biological effects is not well understood, however, there is a growing body of evidence indicating that bile acids can regulate gene expression [ 15 - 18 ]. DCA has been shown to activate a number of mitogenic and apoptosis associated signaling pathways which is consonant with its proposed tumor promoting abilities including the epidermal growth factor receptor and the raf/mek/erk pathway [ 19 - 21 ], protein kinase C [ 22 - 24 ], the AP-1 transcription factor [ 25 - 27 ], and Cox2 [ 17 ] all of which are known to be dysregulated during colon tumorigenesis. Much less is known about the signaling mechanisms activated by UDCA.…”

Bile acids repress E‐cadherin through the induction of Snail and increase cancer invasiveness in human hepatobiliary carcinoma

“…( 8 ) It was reported that the prolonged deregulated expression of activator protein‐1 (AP‐1) activity in colonic cells by certain bile acids contributed to tumor promotion in the colon. ( 9,10 ) Bile acids were also reported to be involved in the induction of cyclooxygenase‐2 (COX‐2), the secretion of matrix metalloproteinase‐2 (MMP‐2) and the migration of colorectal cancer cells. ( 11,12 ) Thus, some kinds of bile acids have been shown to act as tumor promoters in colon cancer.…”