Carcinogenesis Advance Access originally published online on July 4, 2003
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Carcinogenesis, Vol. 24, No. 9, 1541-1548,
September 2003
© 2003 Oxford University Press
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION |
Chemopreventive n-3 fatty acids activate RXR
in colonocytes
1 Faculty of Nutrition, Texas A&M University, College Station, TX 77843, USA
2 Center for Environmental and Rural Health, Texas A&M University, College Station, TX 77843, USA
3 Department of Animal Science, Texas A&M University, College Station, TX 77843, USA
4 Department of Statistics, Texas A&M University, College Station, TX 77843, USA
5 INCELL Corporation, San Antonio, TX 78249, USA
6 To whom correspondence should be addressed Email: r-chapkin{at}tamu.edu
The underlying mechanisms by which n-3 polyunsaturated fatty acids (PUFA) exert a chemopreventive effect in the colon have not been elucidated. Retinoid X receptors (RXR) are a family of nuclear receptors implicated in cancer chemoprevention. Since docosahexaenoic acid (DHA), an n-3 PUFA enriched in fish oil, reduces colonocyte proliferation and enhances apoptosis relative to n-6 PUFA-treated cells, we determined whether DHA can serve as a specific ligand for RXR
activation relative to n-6 PUFA in colonocytes. In a mammalian one-hybrid assay, immortalized young adult mouse colonic (YAMC) cells were co-transfected with a yeast galactose upstream activating sequence (UAS)4-tk-Luciferase (Luc) reporter plasmid, plus either GAL4 DNA-binding domain fused to RXR, retinoic acid receptor or GAL4 alone, followed by an n-3, n-6 or n-9 fatty acid incubation. Luc activity levels were dose-dependently elevated only in n-3 PUFA (DHA)-treated RXR. Since RXR homodimers and RXR/peroxisome proliferator-activated receptor (PPAR) heterodimers bind consensus direct repeat (DR1) motifs, YAMC and NCM460 (a normal human colonic cell line), were respectively, co-transfected with RXR and DR1-Luc, followed by different PUFA treatment. Luc activity levels were increased (P < 0.05) only in DHA groups. The DHA-dependent induction of DR-1-Luc was reduced to basal levels upon RXR antagonist-treatment, with no effect on PPAR
antagonist-treatment. A role for select RXR isoforms in colonocyte biology was also determined by examining nuclear receptor mRNA levels in rat colon following dietary lipid and carcinogen exposure over time. RXR, RXRß and RXR were detected in rat colonic mucosa, and the levels of RXR and RXR were elevated in fish oil (n-3 PUFA) versus corn oil (n-6 PUFA) fed animals after 16 weeks. These data indicate that, RXR, an obligatory component of various nuclear receptors, preferentially binds n-3 PUFA in colonocytes, and that the nuclear receptor targets for PUFA in the colon are modulated by dietary lipid exposure.
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