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Titre du document / Document title

Overexpression and hyperactivity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive to normal arachidonic fatty acid-induced suppression in lipogenic tissues but it is selectively inhibited by tumoricidal α-linolenic and γ-linolenic fatty acids: A novel mechanism by which dietary fat can alter mammary tumorigenesis

Auteur(s) / Author(s)

MENENDEZ Javier A. (1 2) ; ROPERO Santiago (3) ; MEHMI Inderjit (1) ; ATLAS Ella (1 2) ; COLOMER Ramon (4) ; LUPU Ruth (1 2) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Department of Medicine, Evanston Northwestern Research Institute, Evanston, IL, ETATS-UNIS
(2) The Feinberg School of Medicine, Northwestern University, Chicago, IL, ETATS-UNIS
(3) Cancer Epigenetics Laboratory, Program of Molecular Pathology, Spanish National Cancer Research Center (CNIO), Madrid, ESPAGNE
(4) Medical Oncology, Institut Catala d'Oncologia (ICO), Hospital Universitari Dr Josep Trueta, Girona, ESPAGNE

Résumé / Abstract

Activity and expression of fatty acid synthase (FAS), a critical enzyme in the de novo biosynthesis of fatty acids in mammals, is exquisitely sensitive to nutritional regulation of lipogenesis in liver or adipose tissue. Surprisingly, a number of studies have demonstrated hyperactivity and overexpression of FAS (oncogenic antigen-519) in a biologically aggressive subset of human breast carcinomas, suggesting that FAS-dependent neoplastic lipogenesis is unresponsive to nutritional regulation. We have assessed the role of ω-3 and w-6 polyunsaturated fatty acids (PUFAs) on the enzymatic activity and protein expression of tumor-associated FAS in SK-Br3 human breast cancer cells, an experimental paradigm of FAS-overexpressing tumor cells in which FAS enzyme constitutes up to 28%, by weight, of the cytosolic proteins. Of the ω-3 PUFAs tested, α-linolenic acid (ALA) dramatically reduced FAS activity in a dose-dependent manner (up to 61%). ω-3 PUFA docosahexaenoic acid (DHA) demonstrated less marked but still significant inhibitory effects on FAS activity (up to 37%), whereas eicosapentaenoic acid (EPA) was not effective. Of the w-6 fatty acids tested, γ-linolenic acid (GLA) was the most effective dose-dependent inhibitor of FAS activity, with a greater than 75% FAS activity reduction. Remarkably, ω-6 PUFAs linoleic acid (LA) and arachidonic acid (ARA), suppressors of both hepatic and adipocytic FAS-dependent lipogenesis, had no significant inhibitory effects on the activity of tumor-associated FAS in SK-Br3 breast cancer cells. Western blotting studies showed that down-regulation of FAS protein expression tightly correlated with previously observed inhibition of FAS activity, suggesting that ALA-, DHA-, and GLA-induced changes in FAS activity resulted from effects at the protein level. We investigated whether the FAS inhibitory effect of GLA and ω-3 PUFAs correlated with a cytotoxic effect related to a peroxidative mechanism. Measurement of cell viability by MTT assay indicated a significant cellular toxicity after ALA and GLA exposures. Furthermore, we observed a significant correlation between the ability of PUFAs to repress FAS and cause cell toxicity. In the presence of anti-oxidants (vitamin E), ALA and GLA dramatically lost their ability to inhibit FAS activity. Interestingly, a combination of ALA and GLA was FAS inhibitory in an additive manner, and this FAS repression was only partially reversible by vitamin E. In examining the molecular mechanisms underlying resistance of breast cancer-associated FAS to normal dietary fatty acid-induced suppression, a dramatic decrease of FAS accumulation was found after exposure of SK-Br3 cells to mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (MAPK ERK1/2) inhibitor U0126, phosphatidylinositol-3'-kinase (PI-3'K) blocker LY294002, and/or anti-HER-2/neu antibody trastuzumab. Interestingly, a long-term exposure to pharmacological inhibitors of FAS activity cerulenin [(2S,3R) 2,3-epoxy-4-oxo-7E, 10E-dodecadienamide] or C75 also resulted in a significant reduction of FAS accumulation.

Revue / Journal Title

International journal of oncology    ISSN  1019-6439 

Source / Source

2004, vol. 24, no6, pp. 1369-1383 [15 page(s) (article)] (93 ref.)

Langue / Language

Anglais

Editeur / Publisher

Editorial Academy of the International Journal of Oncology, Athens, GRECE  (1992) (Revue)

Mots-clés anglais / English Keywords

Feeding

;

Lipids

;

Mammary gland diseases

;

Enzyme

;

Transferases

;

Acyltransferases

;

Breast cancer

;

Breast

;

Fat

;

Diet

;

Mechanism

;

γ-Linolenic acid

;

Inhibitor

;

Tissue

;

Suppression

;

Fatty acids

;

Antigen

;

Arachidonic acid

;

Carcinogenesis

;

Fatty-acid synthase

;

Malignant tumor

;

Mammary gland

;

Gene overexpression

;

Hyperactivity

;

Mots-clés français / French Keywords

Alimentation

;

Lipide

;

Glande mammaire pathologie

;

Enzyme

;

Transferases

;

Acyltransferases

;

Cancer du sein

;

Sein

;

Matière grasse

;

Régime alimentaire

;

Mécanisme

;

γ-Linolénique acide

;

Inhibiteur

;

Tissu

;

Suppression

;

Acide gras

;

Antigène

;

Arachidonique acide

;

Carcinogenèse

;

Fatty-acid synthase

;

Tumeur maligne

;

Glande mammaire

;

Surexpression génique

;

Hyperactivité

;

Mots-clés espagnols / Spanish Keywords

Alimentación

;

Lípido

;

Glándula mamaria patología

;

Enzima

;

Transferases

;

Acyltransferases

;

Cáncer del pecho

;

Seno

;

Materia grasa

;

Régimen alimentario

;

Mecanismo

;

γ-Linolénico ácido

;

Inhibidor

;

Tejido

;

Supresión

;

Acido graso

;

Antígeno

;

Araquidónico ácido

;

Carcinogénesis

;

Fatty-acid synthase

;

Tumor maligno

;

Glándula mamaria

;

Sobreexpressión genética

;

Hiperactividad

;

Mots-clés d'auteur / Author Keywords

fatty acid synthase

;

oncogenic antigen-519

;

breast cancer

;

γ-linolenic acid

;

polyunsaturated fatty acids

;

vitamin E

;

MAPK

;

PI-3'K/AKT

;

HER-2/neu

;

trastuzumab

;

Localisation / Location

INIST-CNRS, Cote INIST : 26333, 35400011503209.0020

Nº notice refdoc (ud4) : 15679659



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