Disruption of PPARγ signaling results in mouse prostatic intraepithelial neoplasia involving active autophagy

Peroxisome proliferator-activated receptor-gamma (PPAR γ ) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Conditional prostatic epithelial knockout of PPAR γ in mice resulted in focal hyperplasia which developed into mouse prostatic intraepithelial neoplasia (mPIN). The grade of PIN became more severe with time. Electron microscopy (EM) showed accumulated secondary lysosomes containing cellular organelles and debris suggestive of autophagy. Consistent with this analysis the autophagy marker LC-3 was found to be upregulated in areas of PIN in PPAR γ KO tissues. We selectively knocked down PPAR γ 2 isoform in wild-type mouse prostatic epithelial cells and examined the consequences of this in a tissue recombination model. Histopathologically grafted tissues resembled the conditional PPAR γ KO mouse prostates. EM studies of PPAR γ - and PPAR γ 2-deficient epithelial cells in vitro were suggestive of autophagy, consistent with the prostatic tissue analysis. This was confirmed by examining expression of beclin-1 and LC-3. Gene expression profiling in PPAR γ -/ γ 2-deficient cells indicated a major dysregulation of cell cycle control and metabolic signaling networks related to peroxisomal and lysosomal maturation, lipid oxidation and degradation. The putative autophagic phenotypes of PPAR γ -deficient cells could be rescued by re-expression of either γ 1 or γ 2 isoform. We conclude that disruption of PPAR γ signaling results in autophagy and oxidative stress during mPIN pathogenesis.