THE STRESS-RESPONSE PROTEINS POLY(ADP-RIBOSE) POLYMERASE AND NF-KAPPA-B PROTECT AGAINST BILE SALT-INDUCED APOPTOSIS

Bile salts induce apoptosis and are implicated as promoters of colon c ancer. The mechanisms by which bile salts produce these effects are po orly understood. We report that the cytotoxic bile salt, sodium deoxyc holate (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 str ess and DNA damage. The pre-treatment of cells with specific inhibitor s of these proteins [pyrrolidine dithiocarbamate (NF-kappa B inhibitor ) and 3-aminobenzamide (PARP inhibitor)] sensitizes cells to the induc tion of apoptosis by NaDOC, indicating that these stress response path ways are protective in nature. Colon cancer risk has been reported to be associated with resistance to apoptosis. We found an increase in ac tivated NF-kappa B at the base of human colon crypts that exhibit apop tosis resistance. This provides a link between an increased stress res ponse acid colon cancer risk, The implications of these findings with respect to apoptosis and to colon carcinogenesis are discussed.