Carcinogenesis Advance Access originally published online on August 29, 2003
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Carcinogenesis, Vol. 24, No. 11, 1717-1722,
November 2003
© 2003 Oxford University Press
CANCER BIOLOGY |
Activation of PPAR 
in colon tumor cell lines by oxidized metabolites of linoleic acid, endogenous ligands for PPAR
1 Oakland University, Department of Chemistry, Rochester MI 48309-4477, USA, 2 Center for Biotechnology, Karolinska Institute, NOVUM, 141 86 Huddinge, Sweden and 3 Department of Medical Nutrition, Karolinska Institute, NOVUM, 141 86 Huddinge, Sweden
The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) 
plays an important role in the differentiation of intestinal cells and other tissues. Real-time PCR examination of PPAR mRNA for 1, 2 and 3, in Caco-2 and HCT-116 colon cell lines showed that 3 is the most abundant message in both lines. Treatment of Caco-2 cells with sodium butyrate, which induces cell differentiation, also leads to an increase in all three PPAR mRNAs. In contrast, treatment of HCT-116 cells with sodium butyrate, which does not lead to differentiation of these cells, causes a decrease in the amount of all three PPAR mRNAs. Furthermore, the amount of PPAR mRNA is greater in Caco-2 cells than in HCT-116 cells at all times examined. As several oxidative metabolites of linoleic acid, including 13-hydroxyoctadecadienoic acid (13-HODE) and 13-oxooctadecadienoic acid (13-OXO) have been shown to bind PPAR, and there is a strong positive correlation between enzymes for metabolism of linoleate oxidation products, intestinal cell differentiation and the distribution of PPAR, we also performed a detailed investigation of the activation of PPAR by 13-HODE and 13-OXO. For these experiments, Caco-2 and HCT-116 cells were transfected with constructs containing PPAR 1 or 2 then a PPRE-luc reporter construct. Exposure of transfected cells to micromolar concentrations of 13-HODE or 13-OXO produced concentration-dependent increases in luciferase activity. In addition, the two linoleate metabolites activate endogenous PPAR in these cell lines transfected with only PPRE-luc. The data substantiate the contention that oxidation products of linoleic acid are metabolically produced endogenous ligands for PPAR and that PPAR plays an important role in the differentiation of intestinal cells.
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