Increased c-fos mRNA and binding to the AP-1 recognition sequence accompanies the proliferative response to deoxycholate of HT29 cells.
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.
Matheson
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Department of Medical Nutrition, Karolinska Institute, Huddinge, Sweden.
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D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D003840:Deoxycholic Acid / Q000494:pharmacology*; D019073:HT29 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008969:Molecular Sequence Data; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D002756:Cholagogues and Choleretics; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D003840:Deoxycholic Acid; D004247:DNA