Re: Effect of γ-Linolenic Acid on the Transcriptional Activity of the Her-2/neu (erbB-2) Oncogene

Extract

Menendez et al. ( 1 ) recently reported that γ-linolenic acid (GLA) suppresses the expression of the Her-2/neu (erbB-2) oncogene in several cancer cell lines in vitro and that concurrent treatments of Her-2/neu–overexpressing cancer cells with GLA and the anti–Her-2/neu antibody showed synergistic increases in apoptosis and reduced growth and colony formation. These findings are interesting but not surprising because it has previously been shown that several polyunsaturated fatty acids (PUFAs)—GLA, arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)—can kill a variety of tumor cells without harming normal cells, although the sensitivity of tumor cells to the cytotoxic action of these fatty acids varied ( 2 – 4 ) .

In those studies, GLA was the most potent compound; the more highly unsaturated compounds AA, EPA, and DHA were also effective but were much less selective. This finding is surprising because it was thought that GLA and other fatty acids induce apoptosis of tumor cells by a free radical–dependent mechanism and so the higher the unsaturation index, the higher the tumoricidal ability [reviewed in ( 4 ) ]. In addition, GLA produced alterations in tumor cell membrane lipid composition and mitochondrial ultrastructure; induced a substantial decrease in the activity of mitochondrial respiratory chain complexes I + III, IV and mitochondrial membrane potential; increased cytochrome c release from mitochondria; and activated caspases and DNA fragmentation, leading to apoptosis of tumor cells [reviewed in ( 4 ) ]. GLA also decreased the antioxidant content of tumor cells, suppressed the expression of the oncogene Ras and the antiapoptotic gene Bcl-2, and enhanced the expression of p53 ( 5 ) . This action of GLA on gene expression could be related to the ability of its peroxidized products to bind to DNA ( 5 ) .