Carcinogenesis, Vol. 20, No. 6, 969-976,
June 1999
© 1999 Oxford University Press
Cancer Biology |
Effects of colonic lumenal components on AP-1-dependent gene transcription in cultured human colon carcinoma cells
Department of Medical Nutrition, Karolinska Institute, Novum,
S-14186 Huddinge, Sweden
We recently suggested that prolonged deregulated expression of AP-1 activity in colonic cells by bile acids may contribute to tumour promotion in the colon. In the present study, using two human colon carcinoma cell lines, HT-29 and HCT 116, transiently transfected with the AP-1-luciferase reporter construct, we showed that the bile acids, deoxycholate, chenodeoxycholate, ursodeoxycholate and lithocholate, induced AP-1-dependent gene transcription in a dose-dependent manner, whereas cholate was without effect. The greatest effect was observed with deoxycholate, and the ability of this bile acid to induce reporter gene activity was significantly correlated with its ability to induce cell proliferation (r = 0.91, P = 0.01). Cholesterol and the long chain fatty acids, myristate, palmitate and stearate, had no effect on AP-1-dependent gene transcription, whereas the short chain fatty acid, butyrate, exhibited a marked effect. Mindful of the fact that the concentrations of lumenal components that are actually in or entering the epithelial cells in the colon are presumably lower than lumenal values, we considered it of interest to determine the effect of dilution on the capacity of human faecal water to induce AP-1 activity and also cell proliferation. We demonstrated that diluted lipid extracts, from all of the faecal water samples examined, significantly induced AP-1-dependent gene transcription in the colonic cells, and that this effect differed markedly between the extracts. We confirmed that the faecal water lipid extracts, at the same dilution at which they increased AP-1 activity, significantly induced proliferation in the same cell line. These data suggest that lipid components of human faecal water, which is in direct contact with the colon epithelium and may be physiologically more active than the solid phase, can activate AP-1, a transcription factor whose activation has been associated with the promotion of neoplastic transformation.
Abbreviations: AP, activator protein; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethyl sulphoxide; FBS, fetal bovine serum; LCA, lithocholic acid; MTT, 3-(4,5,dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; OAG, sn-1,2-dioctanoylglycerol; PBS, phosphate-buffered saline; PKC, protein kinase C; PMSF, phenylmethylsulphonyl fluoride; RLU, relative light units; TPA, 12-O-tetradecanoylphorbol-13-acetate; UDCA, ursodeoxycholic acid.
1 To whom correspondence should be addressed Email: bjorn.glinghammar{at}mednut.ki.se
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