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Am J Physiol Gastrointest Liver Physiol 284: G996-G1005, 2003. First published February 5, 2003; doi:10.1152/ajpgi.00347.2002
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Vol. 284, Issue 6, G996-G1005, June 2003

Conjugated linoleic acid inhibits cell proliferation and ErbB3 signaling in HT-29 human colon cell line

Han J. Cho1, Woo K. Kim2, Eun J. Kim1, Kyeong C. Jung3, Soochul Park4, Hyun S. Lee1, Angela L. Tyner5, and Jung H. Y. Park1

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-alpha 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-alpha -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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