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

ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Conditional prostatic epithelial knockout of PPARgamma 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 PPARgamma KO tissues. We selectively knocked down PPARgamma2 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 PPARgamma KO mouse prostates. EM studies of PPARgamma- and PPARgamma2-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 PPARgamma-/gamma2-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 PPARgamma-deficient cells could be rescued by re-expression of either gamma1 or gamma2 isoform. We conclude that disruption of PPARgamma signaling results in autophagy and oxidative stress during mPIN pathogenesis.

SUBMITTER: Jiang M

PROVIDER: S-EPMC2821953 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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

Jiang M M Jiang M M Fernandez S S Jerome W G WG He Y Y Yu X X Cai H H Boone B B Yi Y Y Magnuson M A MA Roy-Burman P P Matusik R J RJ Shappell S B SB Hayward S W SW

Cell death and differentiation 20091016 3

Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the interface between cellular lipid metabolism, redox status and organelle differentiation. Conditional prostatic epithelial knockout of PPARgamma 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 autop ...[more]

PMID: 19834493

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Project description:Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina-features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These "Super-Lo-MYC" mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a "paradoxical" increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas.

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

Publications

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

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