Lipid raft disruption by docosahexaenoic acid induces apoptosis in transformed human mammary luminal epithelial cells harboring HER-2 overexpression

Author(s)

Ravacci, Graziela Rosa ^{[1, 2]} ; Brentani, Maria Mitzi ^[1] ; Tortelli, Jr., Tharcisio ^[1] ; Torrinhas, Raquel Suzana M. M. ^[2] ; Saldanha, Tatiana ^[3] ; Torres, Elizabeth Aparecida F. S. ^[4] ; Waitzberg, Dan Linetzky ^[2]

Affiliation

^[1] Univ Sao Paulo, Sch Med, Dept Oncol, BR-01245903 Sao Paulo - Brazil

^[2] Univ Sao Paulo LIM 35, Sch Med, Dept Gastroenterol, BR-01246903 Sao Paulo - Brazil

^[3] Univ Fed Rural Rio de Janeiro, Dept Food Technol, BR-23890000 Rio De Janeiro - Brazil

^[4] Univ Sao Paulo LIM 35, Publ Hlth Fac, BR-01246903 Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF NUTRITIONAL BIOCHEMISTRY; v. 24, n. 3, p. 505-515, MAR 2013.
• Web of Science Citations: 24

Abstract

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. (C) 2013 Elsevier Inc. All rights reserved. (AU)