Skin tumorigenesis results from DNA damage, increased inflammation, and evasion of apoptosis. The peroxisome proliferator-activated receptors (PPARs) can modulate these mechanisms in non-melanoma skin cancer. However, limited data exists regarding the role of PPARs in melanoma. This study examined the effect of proliferator-activated receptor-b/d (PPARβ/δ) and PPARc on cell proliferation, anchorage-dependent clonogenicity, and ectopic xenografts in the UACC903 human melanoma cell line. Stable overexpression of either PPARβ/δ and PPARγ enhanced ligand-induced expression of a PPARβ/δ/PPARc target gene in UACC903 cell lines as compared with controls. The induction of target gene expression by ligand activation of PPARc was not altered by overexpression of PPARβ/δ, or vice versa. Stable overexpression of either PPARβ/δ and PPARγ reduced the percentage of cells in the G1 and S phase of the cell cycle, and increased the percentage of cells in the G2/M phase of the cell cycle in UACC903 cell lines as compared with controls. Ligand activation of PPARβ/δ did not further alter the distribution of cells within each phase of the cell cycle. By contrast, ligand activation of PPARc enhanced these changes in stable UACC903 cells overexpressing PPARc compared with controls. Stable overexpression of either PPARβ/δ and PPARγ and/or ligand activation of either PPARβ/δ and PPARγ inhibited cell proliferation, and anchoragedependent clonogenicity of UACC903 cell lines as compared with controls. Further, overexpression of either PPARβ/δ or PPARc and/or ligand activation of either PPARβ/δ and PPARγ inhibited ectopic xenograft tumorigenicity derived from UACC903 melanoma cells as compared with controls, and this was likely due in part to induction of apoptosis. Results from these studies demonstrate the antitumorigenic effects of both PPARβ/δ and PPARc and suggest that targeting these receptors may be useful for primary or secondary melanoma chemoprevention.
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