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

Abstract

Peroxisome proliferator-activated receptor-gamma (PPARγ) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Conditional prostatic epithelial knockout of PPARγ 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 LC3 was found to be upregulated in areas of PIN in PPARγ KO tissues. We selectively knocked down PPARγ2 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 PPARγ KO mouse prostates. EM studies of PPARγ- and PPARγ2-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 LC3. Gene expression profiling in PPARγ-/γ2-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 PPARγ-deficient cells could be rescued by re-expression of either γ1 or γ2 isoform. We conclude that disruption of PPARγ signaling results in autophagy and oxidative stress during mPIN pathogenesis.

Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

“…The mPrE cell line was originally derived from the mouse prostate epithelial tissues and characterized as epithelial basal cells and 98% positive for stem/progenitor cell markers (31). The PCSCs were originally obtained from a human PCa patient and immortalized by Celprogen (San Pedro, CA) (26,32,33).…”

Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation

“…MEFs were maintained in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum (FBS; GIBCO) and subcultured 1:4 upon reaching confluence. The spontaneously immortalized mouse prostatic epithelial cell line, mPrE, was a generous gift from Dr. Min Jiang [26]. The cell line was maintained in RPMI 1640 medium (GIBCO) supplemented with 5% fetal bovine serum and 1% Antibiotic-Antimycotic (Invitrogen).…”

PTEN Loss and Reactive Microenvironments in Prostate Cancer Progression

“…As shown in Fig. 4, prostatic hyperplasia, a common observation in these animals, is associated with inflammation in the mouse prostates (Jiang et al, 2010b). In BPH patients, stromal nodules have been found to contain increased numbers of T and B lymphocytes (Bierhoff et al, 1996).…”

“…In contrast, the common co-morbidities associated with BPH/LUTS elicit changes in the prostatic metabolic environment, specifically with increased lipid availability and alterations in glucose metabolism consequent to insulin resistance and changes in the IGF/IGFBP axis. Loss of PPARg function in the prostate leads to a number of consequences, including widespread inflammation and hyperplastic growth (Jiang et al, 2010b), with more focal premalignant changes. Due to its central position in balancing cellular metabolism and differentiation, and to the existence and current clinical use of PPARg agonists, PPARg is an attractive target for manipulation in therapeutic strategies to treat prostatic disease.…”

“…Peroxisome proliferator receptor-activated gamma (PPARg) sits at a key balance point in the regulation of cellular metabolism, differentiation and inflammatory responses. Alterations in the activity of this nuclear receptor have potential roles in both BPH and prostate cancer (Jiang et al, 2010b). PPARg activity is amenable to therapeutic manipulation.…”