Activators of peroxisome proliferator-activated receptor-? partially inhibit mouse skin tumor promotion

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Abstract
Several recent reports have suggested that peroxisome proliferator–activated receptors (PPARs) may be involved in the development of neoplasias in different tissue types. The present study was undertaken to determine whether PPARs play a role in skin physiology and tumorigenesis. In an initiation‐promotion study, SENCAR mice treated topically with the PPARα ligands conjugated linoleic acid and 4‐chloro‐6‐(2,3‐xylidino)‐2‐pyrimidinylthioacetic acid (Wy‐14643) exhibited an approximately 30% lower skin tumor yield compared with mice treated with vehicle. The PPARγ and PPARδ activators troglitazone and bezafibrate, respectively, exerted little, if any, inhibitory activity. PPARα was detected in normal and hyperplastic skin and in papillomas and carcinomas by immunohistochemistry. In addition, PPARα, PPARδ/PPARβ, and PPARγ protein levels were analyzed by immunoblotting in normal epidermis and papillomas. Surprisingly, the levels of all three isoforms were increased significantly in tumors as opposed to normal epidermis. In primary keratinocyte cultures, protein levels of PPARα and, to a lesser extent, PPARγ were markedly increased when the cells were induced to differentiate with high‐calcium (0.12 mM) conditions. In addition, we observed that Wy‐14643 enhanced transcriptional activity of a peroxisome proliferator–response element–driven promoter in a mouse keratinocyte cell line. These results demonstrate that keratinocytes express functional PPARα, that PPARα may play a role in differentiation, and that ligands for PPARα are moderately protective against skin tumor promotion. We conclude that selective PPARα ligands may exert their protective role against skin tumor promotion by ligand activation of PPARα. Mol. Carcinog. 29:134–142, 2000.