15-Deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) is a highly specific activator of the peroxisome proliferator-activated receptor gamma (PPAR-gamma). We investigated the effect of 15d-PGJ2 on three human prostate cancer cell lines, LNCaP, DU145, and PC-3. Western blotting demonstrated that PPAR-gamma1 is expressed predominantly in untreated prostate cancer cells. Treatment with 15d-PGJ2 caused an increase in the expression of PPAR-gamma2, whereas PPAR-gamma1 remained at basal levels. PPARs alpha and beta 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-PGJ2. 15d-PGJ2 and other PPAR-gamma activators induced cell death in all three cell lines at concentrations as low as 2.5 microM (similar to the Kd of PPAR-gamma for this ligand), coinciding with an accumulation of cells in the S-phase of the cell cycle. Activators for PPAR-alpha and beta 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 of type 2 (autophagic), nonapoptotic programmed cell death.