Disruption of PPARgamma signaling results in mouse prostatic intraepithelial neoplasia involving active autophagy.
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.
Jiang
M
M
Department of Urologic Surgery, A-1302 MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2765, USA. ming.jiang.1@vanderbilt.edu
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
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure; D020869:Gene Expression Profiling; D007004:Hypoglycemic Agents / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011467:Prostate / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000502:physiology*; D045162:Thiazolidinediones / Q000378:metabolism; D014183:Transplantation, Heterologous
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D020033:Protein Isoforms; D045162:Thiazolidinediones; D000077154:Rosiglitazone