Role of peroxisome proliferator-activated receptor β in conjugated linoleic acid modulation of tumor promoter induced events in mouse skin
Conjugated linoleic acid (CLA) inhibits tumor initiation and promotion in mouse skin of multistage carcinogenesis. Recently our laboratory has shown that CLA is an activator of the peroxisome proliferator-activated receptors (PPARs). Expression and activation of PPARs have been shown to regulate keratinocyte differentiation, and PPAR-β is the predominant isoform expressed in mouse skin. The hypothesis of this project is that CLA inhibits mouse skin tumor promotion through a PPAR-β mediated mechanism. Exogenous CLA (16 μg/mL) was more potent than linoleate (LA) at decreasing the level of 14C-arachidonate (AA) incorporation into cellular phosphatidylcholine (p < 0.05). The tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced 14C-prostaglandin E2 (PGE2) was significantly decreased in cultures pre-treated with CLA/14C-AA compared with cultures pre-treated with LA/ 14C-AA. TPA or acetone (vehicle control) was treated on skins of mice fed a CLA diet (0.0%, 0.5%, 1.0% or 1.5% CLA by weight) for 6 weeks. Dietary CLA (1.5%) significantly decreased TPA-induced epidermal PGE2 synthesis (p < 0.05). Six hour after TPA treatment, dietary CLA significantly reduced the expression of PPAR-β mRNA and keratinocyte lipid binding protein (KLBP), a putative PPAR responsive gene, in mouse epidermis compared with control (0.0% CLA diet, p < 0.05). Eighteen hour after TPA treatment, mice fed a 0.5% diet significantly increased PPAR-β expression. TPA-induced KLBP expression was significantly decreased in mice fed a 1.5% CLA diet when compared with mice fed a 0.0% CLA diet (p < 0.05). Using dimethylbenz[a]anthrancene (initiator)- TPA (promoter) in a mouse skin carcinogenesis experiment. The PPAR ligands, 9Z, 11E-CLA, WY-14,643, bezafibrate and troglitazone or acetone/alcohol vehicle control were topically treated in mouse skin twice prior to each tumor promoter treatment. Mice treated with 9Z, 11E-CLA, and WY-14,643 showed a 30% decrease of skin tumor yield compared with mice treated with vehicle control. PPAR-β and KLBP mRNA expression were induced in papillomas compared with mouse epidermis. However, in mouse skin papillomas and HEL-30, the KLBP and PPAR-β expression did not exhibit differences among PPAR ligand treatments. These data suggest that the antipromoter ability of CLA may be through PPAR-β mediated events during TPA-treatment of mouse skin.
Belury, Purdue University.
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