Bile salt induced stress response pathways

Abstract

Our lab has shown that the bile salt found in the highest concentration in human fecal water, sodium deoxycholate, induces apoptosis in several cell types including Jurkat cells as well as human colonic epithelial cells. We have also found that cells within the normal appearing flat mucosa of patients with a history of colon cancer are relatively resistant to apoptosis induced by NaDOC. The current studies test the hypothesis that sodium deoxycholate induces multiple stress response pathway s that protect against apoptosis. I have tested this hypothesis by developing and analyzing cell lines that are resistant to sodium deoxycholate-induced apoptosis and focusing on two stress-response proteins known to be activated by sodium deoxycholate, poly(ADP-ribose) polymerase (PARP) and the redo-sensitive transcription factor nuclear factor-kappa B (NF-κB). I found that PARP is protective against NaDOC-induced apoptosis, and by independently inhibiting the individual subunits of NF-κB, I found that the p65 subunit is protective, while the p50 subunit is not. Development and subsequent characterization of the NaDOC-resistant HCT-116 cell lines identified several proteins that may be responsible for the development of apoptosis resistance. These proteins will be further tested in future studies.