Nonapoptotic cell death associated with S-phase arrest of prostate cancer cells via the peroxisome proliferator-activated receptor γ ligand, 15-Deoxy-Δ^12,14-prostaglandin J₂

15-Deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) is a highly specific activator of the peroxisome proliferator-activated receptor γ (PPAR-γ). We investigated the effect of 15d-PGJ₂ on three human prostate cancer cell lines, LNCaP, DU145, and PC-3. Western blotting demonstrated that PPAR-γ1 is expressed predominantly in untreated prostate cancer cells. Treatment with 15d-PGJ₂ caused an increase in the expression of PPAR-γ2, whereas PPAR-γ1 remained at basal levels. PPARs α and β were not detected in these cells. Lack of lipid accumulation, increase in CCAAT/enhancer binding proteins (C/EBPs), or expression of aP2 mRNA indicated that adipocytic differentiation is not induced in these cells by 15d- PGJ'2. 15d-PGJ₂ and other PPAR-γ activators induced cell death in all three cell lines at concentrations as low as 2.5 μM (similar to the K(d) of PPAR-γ for this ligand), coinciding with an accumulation of cells in the S-phase of the cell cycle. Activators for PPAR-α and β did not induce cell death. Staining with trypan blue and propidium iodide suggested that, although the plasma membrane appears intact by electron microscopy, disturbances are evident as early as 2 h after treatment. Mitochondrial transmembrane potentials are significantly reduced by 15d-PGJ₂ treatment. In addition, treatment with 15d-PGJ₂ resulted in cytoplasmic changes, which are indicative cell death.