Omega-3 polyunsaturated fatty acids attenuate breast cancer growth through activation of a neutral sphingomyelinase-mediated pathway

Authors

  • Min Wu,

    1. Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Indianapolis, IN, USA
    Current affiliation:
    1. Department of Biochemistry and Molecular Biology, University of North Dakota, PO Box 9037, Grand Forks, ND 58203
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  • Kevin A. Harvey,

    1. Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Indianapolis, IN, USA
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  • Nargiz Ruzmetov,

    1. Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Indianapolis, IN, USA
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  • Zachary R. Welch,

    1. Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Indianapolis, IN, USA
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  • Laura Sech,

    1. Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Indianapolis, IN, USA
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  • Kim Jackson,

    1. Department of Biology, Indiana University-Purdue University, Indianapolis, IN, USA
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  • William Stillwell,

    1. Department of Biology, Indiana University-Purdue University, Indianapolis, IN, USA
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  • Gary P. Zaloga,

    1. Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Indianapolis, IN, USA
    2. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Rafat A. Siddiqui

    Corresponding author
    1. Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Indianapolis, IN, USA
    2. Department of Biology, Indiana University-Purdue University, Indianapolis, IN, USA
    3. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    • Cellular Biochemistry Laboratory, 1800 N. Capitol Ave., Noyes E504, Indianapolis, IN 46202
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    • Fax: +317-962-9369.


Abstract

The effect of fish oils and their active omega-3 fatty acid constituents, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were investigated on breast cancer growth. In in vivo experiments, mice were fed diets that were rich in either omega-3 (fish oil) or omega-6 (corn oil) fatty acids. Three weeks after implantation of MDA-MB-231 breast cancer cells, the tumor volume and weight were significantly lower (p < 0.05) for mice fed the omega-3 diets compared to those fed the omega-6 diets. Dietary fish oil also caused a 40% (p < 0.05) increase in neutral sphingomyelinase (N-SMYase) activity in the tumors. The tumor tissues from fish oil-fed animals expressed elevated p21 (waf1/cip1) mRNA, whereas tumor tissues from corn oil-fed animals exhibited undetectable levels of p21 expression. In in vitro experiments, at concentrations as low as 25 μM, DHA and EPA inhibited the growth of cultured MDA-MB-231 cells in a dose-dependent manner by 20–25% (p < 0.05). N-SMYase activity was also increased by 30–40% (p < 0.05) in the DHA- or EPA-treated cells in which an increase in ceramide formation was observed. DHA and EPA were both observed to enhance membrane bleb formation and also to induce the expression of p21. Omega-3 fatty acids-induced bleb formation and p21 expression were inhibited by the N-SMYase inhibitor GW4869, which also inhibited apoptosis by approximately 40% (p < 0.05). The results suggest that inhibition of breast cancer growth in nude mice by dietary fish oil and inhibition of breast cancer cell growth in culture by treatment with DHA and EPA is mediated by activation of N-SMYase. © 2005 Wiley-Liss, Inc.

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