Lithocholic acid and sulphated lithocholic acid differ in the ability to promote matrix metalloproteinase secretion in the human colon cancer cell line CaCo-2.

Abstract

The human colon carcinoma cell line CaCo-2 has the ability to sulphate the secondary bile acid lithocholic acid (LA), whereas other primary or secondary bile acids were not sulphated [Halvorsen, Kase, Prydz, Gharagozlian, Andresen and Kolset (1999) Biochem. J. 343, 533--539]. To study the biological implications of this modification, CaCo-2 cells were incubated with either LA or sulphated lithocholic acid (3-sulpholithocholic acid, SLA), and in some experiments with taurine-conjugated lithocholic acid. Increased secretion of matrix metalloproteinases (MMPs) correlates with transformation of colon epithelial cells. When CaCo-2 cells were incubated with LA, the secretion of MMP-2 was found to increase approx. 60% when analysed by gelatin zymography, and 80% when analysed by Western blotting. SLA, in contrast, did not affect the level of MMP-2 secretion, and after zymography the level of enzyme activity was 78% of control values after 18 h incubation. The secretion of MMPs is linked to increased cellular invasion and, in tumours, to increased capacity for metastasis. The ability of CaCo-2 cells to invade in a chamber assay was stimulated after exposure to LA, whereas SLA-treated cells did not differ from control cells. LA therefore seems to induce a more invasive CaCo-2 cell phenotype, as judged by the two parameters tested, whereas the sulphated counterpart, SLA, did not have these effects. Sulphation of LA in the colon may be an important mechanism to decrease the potential LA has to promote a malignant epithelial phenotype.