The stress-response proteins poly(ADP-ribose) polymerase and NF-κB protect against bile salt-induced apoptosis

Bile salts induce apoptosis and are implicated as promoters of colon cancer. The mechanisms by which bile salts produce these effects are poorly understood. We report that the cytotoxic bile salt, sodium deoxycholate (NaDOC), activates the key stress response proteins, NF-kappa B and poly(ADP-ribose) polymerase (PARP). The activation of NF-kappa B and PARP, respectively, indicates that bile salts induce oxidative stress and DNA damage. The pre-treatment of cells with specific inhibitors of these proteins [pyrrolidine dithiocarbamate (NF-kappa B inhibitor) and 3-aminobenzamide (PARP inhibitor)] sensitizes cells to the induction of apoptosis by NaDOC, indicating that these stress response pathways are protective in nature. Colon cancer risk has been reported to be associated with resistance to apoptosis. We found an increase in activated NF-kappa B at the base of human colon crypts that exhibit apoptosis resistance. This provides a link between an increased stress response acid colon cancer risk, The implications of these findings with respect to apoptosis and to colon carcinogenesis are discussed.