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1 Division of Life Sciences and 3 Department of Pathology, Hallym University, Chunchon 200 - 702; 2 Department of Food Science and Nutrition, Dankook University, Seoul 140 - 714; 4 Department of Biological Science, Sookmyung Women's University, Seoul, Korea 140 - 742; and 5 Department of Molecular Genetics, University of Illinois College of Medicine, Chicago, Illinois 60607
Conjugated linoleic acid
(CLA) has chemoprotective properties in experimental cancer models, and
in vitro studies have shown that CLA inhibits HT-29 colon cancer cell
growth. ErbB2 and ErbB3 have been implicated in the development of
colon cancer, and both proteins are expressed at high levels in the
HT-29 cell line. Activation of ErbB2/ErbB3 heterodimers is regulated by
the ErbB3 ligand heregulin. To examine CLA regulation of HT-29 cell
proliferation and apoptosis and the influence of CLA on the
ErbB3 signaling pathway, HT-29 cells were cultured in the presence of
CLA and/or heregulin. CLA inhibited DNA synthesis and induced
apoptosis of HT-29 cells. Although the addition of
heregulin-
led to an increase in cell number, it was not able to
counteract the negative growth regulatory effect of CLA.
Immunoprecipitation/Western blot studies revealed that CLA inhibited
heregulin-
-stimulated phosphorylation of ErbB2 and ErbB3,
recruitment of the p85 subunit of phosphoinositide 3-kinase
(PI3-kinase) to the ErbB3 receptor, ErbB3-associated PI3-kinase
activities, and phosphorylation of Akt. CLA decreased ErbB2 and ErbB3
mRNA and protein levels in a dose-dependent manner. In conclusion, we
demonstrate that CLA inhibits cell proliferation and stimulates
apoptosis in HT-29 cells and that this may be mediated by its
ability to downregulate ErbB3 signaling and the PI3-kinase/Akt pathway.
heregulin; phosphoinositide 3-kinase; apoptosis
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