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Lipid raft disruption by docosahexaenoic acid induces apoptosis in transformed human mammary luminal epithelial cells harboring HER-2 overexpression.
MedLine Citation:
PMID:  22749134     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
In HER-2-overexpressing breast cells, HER-2 receptors exist on the cell surface as monomers, homodimers and heterodimers. For signal activation and transduction to occur, HER-2 must be localized to lipid rafts. Therefore, we hypothesized that the amount of lipid rafts on the cell membrane would be a factor in HER-2 signaling. To test this, we used HB4a (an untransformed human mammary epithelial cell line) and HB4aC5.2 cells. HB4aC5.2 cells are HB4a derivatives that have been transfected with five copies of pJ5E.c-ErbB-2 and express approximately 900 times more HER-2 than HB4a cells. In these cells, HER-2 overexpression was accompanied by increased lipid rafts in cell membranes, a hyperactivation of downstream Akt and ERK1/2 proteins, and an increased rate of cell growth compared to HB4a. In addition, HER-2 overexpression was associated with an increased activation of FASN, a key enzyme involved in cellular lipogenesis. Its final product, palmitate, is frequently used to synthesize lipid rafts. We further hypothesized that treatment with docosahexaenoic acid (DHA), an omega-3 fatty acid, would disrupt the lipid rafts and lead to a growth arrest. In HB4aC5.2 cells, but not HB4a cells, we found that DHA treatment disrupted lipid raft; inhibited HER-2 signaling by decreasing activation of Akt, ERK1/2 and FASN proteins; and induced apoptosis. Although little is known about lipid rafts, our data support the idea that disturbances in these microdomains induced by DHA may represent a useful tool for controlling the signaling initiated by HER-2 receptors and its therapeutic potential in the treatment of HER-2 positive breast cancer.
Authors:
Graziela Rosa Ravacci; Maria Mitzi Brentani; Tharcisio Tortelli; Raquel Suzana M M Torrinhas; Tatiana Saldanha; Elizabeth Aparecida F S Torres; Dan Linetzky Waitzberg
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-27
Journal Detail:
Title:  The Journal of nutritional biochemistry     Volume:  -     ISSN:  1873-4847     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-7-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9010081     Medline TA:  J Nutr Biochem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Department of Oncology Medical School, University of São Paulo, 01246-903 São Paulo, Brazil; Department of Gastroenterology Medical School, University of São Paulo-LIM 35, 01246-903 São Paulo, Brazil.
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