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Deoxycholyltaurine rescues human colon cancer cells from apoptosis by activating EGFR‐dependent PI3K/Akt signaling
Author(s) -
Raufman JeanPierre,
Shant Jasleen,
Guo Chang Yue,
Roy Sanjit,
Cheng Kunrong
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21332
Subject(s) - protein kinase b , pi3k/akt/mtor pathway , cancer research , phosphorylation , signal transduction , cell growth , microbiology and biotechnology , kinase , apoptosis , epidermal growth factor receptor , epidermal growth factor , chemistry , biology , cancer , medicine , biochemistry , receptor
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‐α‐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‐κB, 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. J. Cell. Physiol. 215: 538–549, 2008. © 2007 Wiley‐Liss, Inc.