Recent studies indicate that secondary
bile acids promote
colon cancer cell proliferation but their role in maintaining cell survival has not been explored. We found that
deoxycholyltaurine (DCT) markedly attenuated both unstimulated and
TNF-alpha-stimulated programmed cell death in
colon cancer cells by a
phosphatidylinositol 3-kinase (PI3K)-dependent mechanism. To examine the role of
bile acids and PI3K signaling in maintaining
colon cancer cell survival, we explored the role of signaling downstream of
bile acid-induced activation of the
epidermal growth factor receptor (EGFR) in regulating both apoptosis and proliferation of HT-29 and H508 human
colon cancer cells. DCT caused dose- and time-dependent Akt (Ser(473)) phosphorylation, a commonly used marker of activated PI3K/Akt signaling. Both EGFR
kinase and PI3K inhibitors attenuated DCT-induced Akt phosphorylation and Akt activation, as demonstrated by reduced phosphorylation of a GSK-3-paramyosin substrate. Transfection of HT-29 cells with
kinase-dead EGFR (K721M) reduced DCT-induced Akt phosphorylation. In HT-29 cells, EGFR and PI3K inhibitors as well as transfection with dominant negative AKT attenuated DCT-induced cell proliferation. DCT-induced PI3K/Akt activation resulted in downstream phosphorylation of
GSK-3 (Ser(21/9)) and BAD (Ser(136)), and nuclear translocation (activation) of
NF-kappaB, thereby confirming that DCT-induced activation of PI3K/Akt signaling regulates both proproliferative and prosurvival signals. Collectively, these results indicate that DCT-induced activation of post-EGFR PI3K/Akt signaling stimulates both
colon cancer cell survival and proliferation.