Journal of Biological Chemistry
Volume 278, Issue 34, 22 August 2003, Pages 31861-31870
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Mechanisms of Signal Transduction
Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells: A ROLE FOR CARDIOLIPIN*

https://doi.org/10.1074/jbc.M300190200Get rights and content
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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 β-oxidation with the AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-β-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.

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*

This work was supported in part by Studentships from the Fonds Québécois de la Recherche sur la Nature et les Technologies (to S. H.), from the Association du Diabète du Québec (to W. E.-A.) from the Fondation Bourgie/Institut du Cancer de Montréal (to E. P.), and by research grants from the Montreal Breast Cancer Foundation, the Canadian Cancer Etiology Research Network, and the Fondation René Malo/Institut du Cancer de Montréal (to M. P., E. J., and Y. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Distinguished Scientist Award from the Canadian Institutes of Health Research.