Autophagy in nuclear receptor PPARγ-deficient mouse prostatic carcinogenesis

Jiang, Ming; Jerome, W.G.; Hayward, Simon W.

doi:10.4161/auto.6.1.10700

Cited by 20 publications

(16 citation statements)

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“…(Fig. s3A and B) (13, 14). These data suggest that the crosstalk between macrophages and prostate epithelial cells was able to enhance STAT3 activation in prostate epithelial cells, regardless of whether the macrophages originated from an established cell line or murine bone marrow.…”

Section: Resultsmentioning

confidence: 99%

Infiltrating Macrophages Promote Prostate Tumorigenesis via Modulating Androgen Receptor-Mediated CCL4–STAT3 Signaling

et al. 2013

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Infiltrating macrophages are a key component of inflammation during tumorigenesis, but the direct evidence of such linkage remains unclear. We report here that persistent co-culturing of immortalized prostate epithelial cells with macrophages, without adding any carcinogens, induces prostate tumorigenesis, and that induction involves the alteration of signaling of macrophage androgen receptor (AR)-inflammatory chemokine CCL4-STAT3 activation as well as epithelial-to-mesenchymal transition (EMT) and down-regulation of p53/PTEN tumor suppressors. In vivo studies further showed that PTEN+/− mice lacking macrophage AR developed far fewer prostatic intraepithelial neoplasia (PIN) lesions, supporting an in vivo role for macrophage AR during prostate tumorigenesis. CCL4 neutralizing antibody effectively blocked macrophage-induced prostate tumorigenic signaling, and targeting AR via an AR degradation enhancer, ASC-J9®, reduced CCL4 expression and xenografted tumor growth in vivo. Importantly, CCL4 upregulation was associated with increased Snail expression and down-regulation of p53/PTEN in high-grade PIN and prostate cancer. Together, our results identify the AR-CCL4-STAT3 axis as key regulators during prostate tumor initiation and highlight the important roles of infiltrating macrophages and inflammatory cytokines for the prostate tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Infiltrating Macrophages Promote Prostate Tumorigenesis via Modulating Androgen Receptor-Mediated CCL4–STAT3 Signaling

et al. 2013

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“…A link between IBD and lysosomal alterations have been suggested earlier [16]. More recently, disruption of PPAR γ in mice resulted in focal hyperplasia, accumulation of lysosomes and dysregulation of pathways related to lysosomal maturation in a prostatic cancer model [17], [18]. Cathepsins are lysosomal acid hydrolases whose transcription is enhanced in colonic mucosa in response to dietary DSS.…”

Section: Discussionmentioning

confidence: 99%

Immunoregulatory Actions of Epithelial Cell PPAR γ at the Colonic Mucosa of Mice with Experimental Inflammatory Bowel Disease

et al. 2010

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BackgroundPeroxisome proliferator-activated receptors are nuclear receptors highly expressed in intestinal epithelial cells (IEC) and immune cells within the gut mucosa and are implicated in modulating inflammation and immune responses. The objective of this study was to investigate the effect of targeted deletion of PPAR γ in IEC on progression of experimental inflammatory bowel disease (IBD).Methodology/Principal FindingsIn the first phase, PPAR γ flfl; Villin Cre- (VC-) and PPAR γ flfl; Villin Cre+ (VC+) mice in a mixed FVB/C57BL/6 background were challenged with 2.5% dextran sodium sulfate (DSS) in drinking water for 0, 2, or 7 days. VC+ mice express a transgenic recombinase under the control of the Villin-Cre promoter that causes an IEC-specific deletion of PPAR γ. In the second phase, we generated VC- and VC+ mice in a C57BL/6 background that were challenged with 2.5% DSS. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to phenotypically characterize lymphocyte and macrophage populations in blood, spleen and mesenteric lymph nodes. Global gene expression analysis was profiled using Affymetrix microarrays. The IEC-specific deficiency of PPAR γ in mice with a mixed background worsened colonic inflammatory lesions, but had no effect on disease activity (DAI) or weight loss. In contrast, the IEC-specific PPAR γ null mice in C57BL/6 background exhibited more severe inflammatory lesions, DAI and weight loss in comparison to their littermates expressing PPAR γ in IEC. Global gene expression profiling revealed significantly down-regulated expression of lysosomal pathway genes and flow cytometry results demonstrated suppressed production of IL-10 by CD4+ T cells in mesenteric lymph nodes (MLN) of IEC-specific PPAR γ null mice.Conclusions/SignificanceOur results demonstrate that adequate expression of PPAR γ in IEC is required for the regulation of mucosal immune responses and prevention of experimental IBD, possibly by modulation of lysosomal and antigen presentation pathways.

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“…Recent studies have shown that enhanced autophagy may function as a tumor suppressing mechanism, and defects in autophagy can promote cancer (15). The mechanisms of autophagic cell death can be used as an effective method for cancer prevention and treatment (16).…”

Section: Human Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Autophagy-related Gene 7 (ATG7) and Reactive Oxygen Species/Extracellular Signal-regulated Kinase Regulate Tetrandrine-induced Autophagy in Human Hepatocellular Carcinoma

Gong

Chen

Yao

et al. 2012

Journal of Biological Chemistry

125

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Background: Tetrandrine exhibits antitumor effects and causes liver cancer apoptosis. Results: Tetrandrine induced hepatocellular carcinoma autophagy via ATG7 and ROS/ERK in vitro, in vivo, and in Caenorhabditis elegans muscle cells. Conclusion: Tetrandrine is a potent autophagy agonist. Significance: Tetrandrine may be a promising clinical chemotherapeutic agent for human hepatocellular carcinoma.

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Autophagy in nuclear receptor PPARγ-deficient mouse prostatic carcinogenesis

Cited by 20 publications

References 0 publications

Infiltrating Macrophages Promote Prostate Tumorigenesis via Modulating Androgen Receptor-Mediated CCL4–STAT3 Signaling

Infiltrating Macrophages Promote Prostate Tumorigenesis via Modulating Androgen Receptor-Mediated CCL4–STAT3 Signaling

Immunoregulatory Actions of Epithelial Cell PPAR γ at the Colonic Mucosa of Mice with Experimental Inflammatory Bowel Disease

Autophagy-related Gene 7 (ATG7) and Reactive Oxygen Species/Extracellular Signal-regulated Kinase Regulate Tetrandrine-induced Autophagy in Human Hepatocellular Carcinoma

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