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Overexpressed ß-Catenin Blocks Nitric Oxide–Induced Apoptosis in Colonic Cancer Cells

Mucosal Inflammation Research Group and Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada

Requests for reprints: Wallace K. MacNaughton, Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta, Canada T2N 4N1. Phone: 1-403-220-5882; Fax: 1-403-283-3840; Email: wmacnaug{at}ucalgary.ca.

ß-Catenin plays an important role in colonic tumorigenesis whereas inducible nitric oxide synthase and nitric oxide are elevated in colonic inflammation. Resistance of colonic epithelial cells to the induction of apoptosis may contribute to tumor development. Nitric oxide can stimulate apoptosis and, paradoxically, is implicated in the development of colon cancer. Our hypothesis was that ß-catenin could increase the resistance of colonic cancer cells to nitric oxide–induced apoptotic cell death. Here we show, using a ß-catenin overexpression system, that increased cytosolic ß-catenin renders colonic epithelial cells more resistant to nitric oxide–induced apoptotic cell death, independently of nitric oxide–induced accumulation of p53. Furthermore, we show that this occurs through inhibition of nitric oxide–induced release of cytochrome c from mitochondria and by blocking both the nitric oxide–induced suppression of the antiapoptotic protein, Bcl-xL, and the phosphorylation of Akt. We contend that increased nitric oxide production, such as that which occurs in chronic colonic inflammation, may select the cells with oncogenic mutant ß-catenin regulatory genes and contribute to human colonic carcinogenesis and tumor progression.

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