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© The Author 2006. Published by Oxford University Press.
CORRESPONDENCE |
Re: Effect of 
-Linolenic Acid on the Transcriptional Activity of the Her-2/neu (erbB-2) Oncogene
Correspondence to: Undurti N. Das, MD, FAMS, UND Life Sciences, 13800 Fairhill Rd., #321, Shaker Heights, OH 44120 (e-mail: undurti{at}hotmail.com).
Menendez et al. (1) recently reported that 
-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).
The ability of GLA to suppress the expression of the Her-2/neu (erbB-2) oncogene could be due to the binding of GLA and/or its peroxidized products to DNA. Her-2/neu (erbB-2) reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide in breast cancer cells by decreasing production of the free radical nitric oxide (NO) (6). Further, the cyclooxygenase-2 (COX-2) product prostaglandin E2 reverses the induction of apoptosis and NO production induced by the combination of N-(4-hydroxyphenyl)retinamide and COX-2 inhibitor in breast cancer cells (7). This finding suggests that the Her-2/neu (erbB-2) oncogene behaves as an antioxidant and that the increased COX-2 activity seen in breast cancer cells is a protective mechanism developed by tumor cells to escape from the tumoricidal action of PUFAs. This observation implies that the activity of fatty acid-CoA ligase (FACL), another PUFA-utilizing enzyme, may be increased in drug-resistant tumor cells. The relative resistance of cancer cells to apoptosis could be due to overexpression of COX-2 and FACL, which could serve as "sinks" for unesterified PUFAs. If so, reduction of apoptosis could be inversely correlated with the cellular level of PUFAs. The apoptotic response of tumor cells that overexpress FACL and COX-2 could be restored by the addition of nonsteroidal anti-inflammatory drugs and PUFAs. Thus, it is likely that one mechanism by which trastuzumab inhibits tumor growth is by enhancing free radical generation by blocking the Her-2/neu (erbB-2) oncogene. This mechanism could explain why a combination of GLA and trastuzumab led to synergistic increases in apoptosis.
REFERENCES
(1) Menendez JA, Vellon L, Colomer R, Lupu R. Effect of -linolenic acid on the transcriptional activity of the Her-2/neu (erbB-2) oncogene. J Natl Cancer Inst 2005;97:1611–5.
(2) Begin ME, Ells G, Das UN, Horrobin D F. Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst 1986;77:1053–62.[Web of Science][Medline]
(3) Begin ME, Das UN, Ells G. Cytotoxic effects of essential fatty acids (EFA) in mixed cultures of normal and malignant human cells. Prog Lipid Res 1986;25:573–6.[CrossRef]
(4) Das UN. From bench to the clinic: -linolenic acid therapy of human gliomas. Prostaglandins Leukot Essent Fatty Acids 2004;70:539–52.[Medline]
(5) Das UN. Essential fatty acids, lipid peroxidation and apoptosis. Prostaglandins Leukot Essent Fatty Acids 1999;61:157–63.[CrossRef][Web of Science][Medline]
(6) Simeone AM, Broemeling LD, Rosenblum J, Tari AM. HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production. Oncogene 2003;22:6739–47.[CrossRef][Web of Science][Medline]
(7) Simeone AM, Li Y-J, Broemeling LD, Johnson MM, Tuna M, Tari AM. Cyclooxygenase-2 is essential for HER2/neu to suppress N-(4-hydroxyphenyl)retinamide apoptotic effects in breast cancer cells. Cancer Res 2004;64:1224–8.
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-Linolenic Acid on the Transcriptional Activity of the Her-2/neu (erbB-2) Oncogene
J Natl Cancer Inst 2006 98: 718-720.
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