title: Saturated fatty acid-induced apoptosis in MDA-MB-231 breast cancer cells. A role for cardiolipin.
abstract: Little is known about the biochemical basis of the action of free fatty acids (FFA) on breast cancer cell proliferation and apoptosis. Here we report that unsaturated FFAs stimulated the proliferation of human MDA-MB-231 breast cancer cells, whereas saturated FFAs inhibited it and caused apoptosis. Saturated FFA palmitate decreased the mitochondrial membrane potential and caused cytochrome c release. Palmitate-induced apoptosis was enhanced by the fat oxidation inhibitor etomoxir, whereas it was reduced by fatty-acyl CoA synthase inhibitor triacsin C. The non-metabolizable analog 2-bromopalmitate was not cytotoxic. This indicates that palmitate must be metabolized to exert its toxic effect but that its action does not involve fat oxidation. Pharmacological studies showed that the action of palmitate is not mediated via ceramides, reactive oxygen species, or changes in phosphatidylinositol 3-kinase activity. Palmitate caused early enhancement of cardiolipin turnover and decreased the levels of this mitochondrial phospholipid, which is necessary for cytochrome c retention. Cosupplementation of oleate, or increasing beta-oxidation with the AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside, both restored cardiolipin levels and blocked palmitate-induced apoptosis. Oleate was preferentially metabolized to triglycerides, and oleate cosupplementation channeled palmitate esterification processes to triglycerides. Overexpression of Bcl-2 family members blocked palmitate-induced apoptosis. The results provide evidence that a decrease in cardiolipin levels and altered mitochondrial function are involved in palmitate-induced breast cancer cell death. They also suggest that the antiapoptotic action of oleate on palmitate-induced cell death involves both restoration of cardiolipin levels and redirection of palmitate esterification processes to triglycerides.
authors.affiliation: Molecular Nutrition Unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and the Institut du Cancer de Montréal, Université de Montréal, Québec H2L 4M1, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Hardy
authors.forename: Wissal
authors.initials: W
authors.lastname: El-Assaad
authors.forename: Ewa
authors.initials: E
authors.lastname: Przybytkowski
authors.forename: Erik
authors.initials: E
authors.lastname: Joly
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.forename: Yves
authors.initials: Y
authors.lastname: Langelier
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D050356:Lipid Metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D005227:Fatty Acids; D019869:Phosphatidylinositol 3-Kinases