Autophagy in nuclear receptor PPARγ-deficient mouse prostatic carcinogenesis

Abstract

Peroxisome proliferator-activated receptor-gamma (PPARγ) is a major modulator of cellular lipid metabolism and organelle differentiation. To understand whether autophagy is involved in the processes of dysregulated fatty acid oxidation and induced oxidative stress accompanying prostatic carcinogenesis, we characterized in vitro and in vivo models of PPARγ- and PPARγ2-deficiency in mouse prostate epithelia. Autophagy accompanied the altered cellular proliferation and de-differentiation that resulted in PPARγ-/γ2-deficient mouse prostatic intraepithelial neoplasia (mPIN). Electron microscopy showed accumulated defective lysosomes and autophagic vacuoles in PPARγ-/γ2-deficient cells, suggestive of autophagy. Gene expression profiling indicated a major dysregulation of cell cycle control and metabolic signaling networks related to peroxisomal, mitochondrial and lysosomal maturation, lipid oxidation and degradation. Further, the putative autophagic phenotypes of PPARγ-null cells could be rescued by re-expression of either the PPARγ1 or -γ2 isoform. Our paper examines the links between autophagy and PPARγ-related subcellular and histopathological changes taking place during murine prostatic carcinogenesis. © 2010 Landes Bioscience.