Characterization of bile salt-induced apoptosis in colon cancer cell lines

Bile salts have been shown to be involved in the etiology of colorectal can cer. Although there is a Large body of evidence for bile salts as a cocarci nogen in azoxymethane-induced colorectal cancer, bile salt-induced apoptosi s of colorectal cancer cells has not yet been studied in detail. Therefore, we investigated the effects of different bile salts on apoptosis and apopt otic signaling in colon cancer cell lines. Incubation of colorectal cancer cell lines with physiological concentration s of deoxycholic acid led to a dramatic induction of apoptosis. Caspase cle avage and caspase activation occurred as early as 30 min after the addition of deoxycholate. Caspase-2 (Ich-1, Nedd2), caspase-3 (CPP-32, YAMA, Apopai n), caspase-7 (Mch-3, ICE-LAP-3), and caspase-8 (FLICE, Mach-1, Mch5) are a ctivated in HT-29, whereas caspase-1 (ICE) remained intact. Caspase activat ion and cellular apoptosis induced by bile salts were reversed by broad spe ctrum and selective caspase inhibitors. As opposed to hepatocyte death medi ated by bile acids, CD95 was not involved in deoxycholate-induced apoptosis . The cytoprotective effect of ursodeoxycholic acid in hepatocytes or other tumor cell lines, which Is mediated by inhibiting the mitochondrial permea bility transition, was not observed in colon cancer cell lines as well. Thi s points to distinct intracellular functions of ursodeoxycholate in differe nt cancer cell types. Here we describe the specificity of bile salt-induced apoptosis in colon ca ncer cell lines. Differences from hepatocytes are shown. Bile acid-specific caspase activation is part of the apoptotic pathway induced by bile salts in colon cancer cell lines. Furthermore, a lack of cytoprotective function of ursodeoxycholate in these cells is demonstrated. Our data raise question s as to the role of bile salts in colorectal carcinogenesis.