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Acetyl-CoA Carboxylase Is Essential to Breast Cancer Cell Survival

¹ Centre National de la Recherche Scientifique-FRE 2939, Institut Gustave Roussy, Villejuif, France and ² Centre National de la Recherche Scientifique-Unité Mixte de Recherche 5201, Faculté de Médecine Rockefeller, Lyon, France

Requests for reprints: Virginie Joulin, Centre National de la Recherche Scientifique-FRE 2939, Institut Gustave Roussy, 93, rue C. Desmoulins, 94805 Villejuif, France. Phone: 33-1-42-11-40-74; Fax: 33-1-42-11-52-61; E-mail: joulin{at}igr.fr.

Activation of de novo fatty acid synthesis is a characteristic feature of cancer cells. We have recently described an interaction between acetyl-CoA carboxylase (ACC), a key enzyme in fatty acid synthesis, and BRCA1, which indicates a possible connection between lipid synthesis and genetic factors involved in susceptibility to breast and ovarian cancers. For this reason, we explored the role of ACC in breast cancer cell survival using an RNA interference (RNAi) approach. We show that specific silencing of either the ACC or the fatty acid synthase (FAS) genes in cancer cells results in a major decrease in palmitic acid synthesis. Depletion of the cellular pool of palmitic acid is associated with induction of apoptosis concomitant with the formation of reactive oxygen species (ROS) and mitochondrial impairment. Expression of a small interfering RNA (siRNA)–resistant form of ACC mRNA prevented the effect of ACC-RNAi but failed to prevent the effect of FAS gene silencing. Furthermore, supplementation of the culture medium with palmitate or with the antioxidant vitamin E resulted in the complete rescue of cells from both ACC and FAS siRNA–induced apoptosis. Finally, human mammary epithelial cells are resistant to RNAi against either ACC or FAS. These data confirm the importance of lipogenesis in cancer cell survival and indicate that this pathway represents a key target for antineoplastic therapy that, however, might require specific dietary recommendation for full efficacy. (Cancer Res 2006; 66(10): 5287-94)

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