Carcinogenesis Advance Access published online on June 23, 2005
Carcinogenesis, doi:10.1093/carcin/bgi163
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1 Faculty of Nutrition, Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX 77843
* To whom correspondence should be addressed. Docosahexaenoic acid (DHA, 22:6n-3) from fish oil, and butyrate, a fiber fermentation product, work coordinately to protect against colon tumorigenesis in part by inducing apoptosis. We have recently demonstrated that dietary DHA is incorporated into mitochondrial membrane phospholipids, thereby enhancing oxidative stress induced by butyrate metabolism. In order to elucidate the subcellular origin of oxidation induced by DHA and butyrate, immortalized mouse colonocytes (YAMC) were treated with 0-200 µM DHA or linoleic acid (LA, 18:2n-6; control) for 72 h with or without 5 mM butyrate for the final 24 h. Cytosolic reactive oxygen species (ROS), membrane lipid oxidation, and mitochondrial membrane potential (MP), were measured by live-cell fluorescence microscopy. After 24 h of butyrate treatment, DHA primed cells exhibited a 151% increase in lipid oxidation (p<0.01), compared to no butyrate treatment, which could be blocked by a mitochondria-specific antioxidant, MitoQ (p<0.05). Butyrate treatment of LA pretreated cells did not show any significant effect. In the absence of butyrate, DHA treatment, compared to LA, increased resting MP by 120% (p<0.01). In addition, butyrate-induced MP dissipation was 21% greater in DHA primed cells as compared to LA at 6 h. This effect was reversed by preincubation with inhibitors of the mitochondrial permeability transition (MPT) pore, cyclosporin A or bongkrekic acid (1 µM). The functional importance of these events is supported by the demonstration that DHA and butyrate-induced apoptosis is blocked by MitoQ. These data indicate that DHA and butyrate potentiate mitochondrial lipid oxidation and the dissipation of MP which contribute to the induction of apoptosis.
Received April 17, 2005
Revised June 3, 2005
Accepted June 15, 2005
CANCER BIOLOGY
The role of docosahexaenoic acid in mediating mitochondrial membrane lipid oxidation and apoptosis in colonocytes
2 Center for Environmental and Rural Health, Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX 77843
3 Center for Environmental and Rural Health, Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX 77843; Faculty of Toxicology, Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX 77843
4 Department of Statistics, Texas A&M University, College Station, TX 77843
5 Faculty of Nutrition, Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX 77843; Center for Environmental and Rural Health, Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX 77843
6 Faculty of Nutrition, Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX 77843; Center for Environmental and Rural Health, Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX 77843; Faculty of Toxicology, Department of Veterinary Integrated Biosciences, Texas A&M University, College Station, TX 77843
Robert S. Chapkin, E-mail: r-chapkin{at}tamu.edu
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