MP70-13 DEPLETION OF PMEPA1 GENE CONFERS INCREASED CELL PROLIFERATION IN MOUSE PROSTATE EPITHELIUM

Abstract Background The IκB kinase (IKK) complex, comprising the two enzymes IKKα and IKKβ, is the main activator of the inflammatory transcription factor NF-κB, which is constitutively active in many cancers. While several connections between NF-κB signaling and the oncogene c-Myc have been shown, functional links between the signaling molecules are still poorly studied. Methods Molecular interactions were shown by co-immunoprecipitation and FRET microscopy. Phosphorylation of c-Myc was shown by kinases assays and its activity by improved reporter gene systems. CRISPR/Cas9-mediated gene knockout and chemical inhibition were used to block IKK activity. The turnover of c-Myc variants was determined by degradation in presence of cycloheximide and by optical pulse-chase experiments.. Immunofluorescence of mouse prostate tissue and bioinformatics of human datasets were applied to correlate IKKα- and c-Myc levels. Cell proliferation was assessed by EdU incorporation and apoptosis by flow cytometry. Results We show that IKKα and IKKβ bind to c-Myc and phosphorylate it at serines 67/71 within a sequence that is highly conserved. Knockout of IKKα decreased c-Myc-activity and increased its T58-phosphorylation, the target site for GSK3β, triggering polyubiquitination and degradation. c-Myc-mutants mimicking IKK-mediated S67/S71-phosphorylation exhibited slower turnover, higher cell proliferation and lower apoptosis, while the opposite was observed for non-phosphorylatable A67/A71-mutants. A significant positive correlation of c-Myc and IKKα levels was noticed in the prostate epithelium of mice and in a variety of human cancers. Conclusions Our data imply that IKKα phosphorylates c-Myc on serines-67/71, thereby stabilizing it, leading to increased transcriptional activity, higher proliferation and decreased apoptosis.

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Interaction of Retinoic Acid and 3-Methylcholanthrene on the Fine Structure of Mouse Prostate Epithelium in Vitro

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/63.2.485 ◽

1979 ◽

Keyword(s):

Fine Structure ◽

Retinoic Acid ◽

Mouse Prostate ◽

Prostate Epithelium

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Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0712021105 ◽

2008 ◽

Vol 105 (7) ◽

pp. 2521-2526 ◽

Cited By ~ 61

Author(s):

C. K. Ratnacaram ◽

M. Teletin ◽

M. Jiang ◽

X. Meng ◽

P. Chambon ◽

...

Keyword(s):

Adult Mouse ◽

Prostatic Adenocarcinoma ◽

Mouse Prostate ◽

Prostate Epithelium

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The Metaplastic Effects of Estrogen on Mouse Prostate Epithelium: Proliferation of Cells with Basal Cell Phenotype1

Endocrinology ◽

10.1210/endo.142.6.8171 ◽

2001 ◽

Vol 142 (6) ◽

pp. 2443-2450 ◽

Cited By ~ 51

Author(s):

Gail P. Risbridger ◽

Hong Wang ◽

Mark Frydenberg ◽

Gerald Cunha

Keyword(s):

Basal Cell ◽

Mouse Prostate ◽

Prostate Epithelium

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RUNX1 marks a luminal castration-resistant lineage established at the onset of prostate development

eLife ◽

10.7554/elife.60225 ◽

2020 ◽

Vol 9 ◽

Author(s):

Renaud Mevel ◽

Ivana Steiner ◽

Susan Mason ◽

Laura CA Galbraith ◽

Rahima Patel ◽

...

Keyword(s):

Proximal Region ◽

Lineage Tracing ◽

Genetic Lineage ◽

Prostate Development ◽

Castration Resistant ◽

Mouse Prostate ◽

Luminal Cells ◽

Genetic Lineage Tracing ◽

Prostate Epithelium

The characterization of prostate epithelial hierarchy and lineage heterogeneity is critical to understand its regenerative properties and malignancies. Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct from the previously identified NKX3.1+ luminal castration-resistant cells. Using scRNA-seq profiling and genetic lineage tracing, we show that RUNX1+ PLCs are unaffected by androgen deprivation, and do not contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a transcriptionally similar RUNX1+ population emerges at the onset of embryonic prostate specification to populate the proximal region of the ducts. Collectively, our results reveal that RUNX1+ PLCs is an intrinsic castration-resistant and self-sustained lineage that emerges early during prostate development and provide new insights into the lineage relationships of the prostate epithelium.

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Host versus cell-dependent effects of β-Arrestin-1 expression in prostate tumorigenesis

Carcinogenesis ◽

10.1093/carcin/bgab021 ◽

2021 ◽

Author(s):

Timothy O Adekoya ◽

Nikia Smith ◽

Ariel J Thomas ◽

Tonya S Lane ◽

Nija Burnette ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Tumor Growth ◽

Receptor Expression ◽

Androgen Independence ◽

Prostate Tumorigenesis ◽

Akt Phosphorylation ◽

Mouse Prostate ◽

Cancer Aggressiveness ◽

Prostate Cancer Development

Abstract Prostate cancer constitutes a serious health challenge and remains one of the main causes of cancer-related death among men. The more aggressive form of the disease has been attributed to androgen independence; resulting in lack of response to androgen deprivation therapy and sustained activation of other growth pathways. The scaffold proteins β-arrestin 1 and 2 (βarr1 and βarr2) which are known to mediate G protein-coupled receptor desensitization and internalization, were also shown to modulate prostate tumorigenesis. βarr1 is significantly overexpressed (>4 fold) in prostate cancer cells relative to βarr2. In this study, we investigated the effect of βarr1 overexpression in prostate cancer development and progression using the mouse and human PCa cell xenografts, and autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) models deficient in β-arrestins Depletion of βarr1 in TRAMP mice (TRAMP/βarr1 -/-) increased PCa growth and decreased overall survival relative to control TRAMP or TRAMP/βarr2 -/- animals. Prostate tissues from TRAMP/βarr1 -/- tumors displayed an increase in androgen receptor expression whereas overexpression of βarr1 in TRAMP-C1 (TRAMP-C1-βarr1-GFP) which derived from TRAMP decreased AR expression, cell proliferation and tumor growth in nude mice xenografts, relative to control TRAMP-C1-GFP. Knockdown of βarr1 expression in human MDA PCa 2b cells (MDA PCa 2b-βarr1 -/-) also decreased AR expression cell proliferation and tumor growth relative to control (MDA PCa 2b-Sham) cells. Interestingly, both TRAMP-C1-βarr1-GFP and MDA PCa 2b-βarr1 -/- xenografts showed a decrease in AKT phosphorylation, but an increase MAPK activation. Altogether, the data indicate that the effect of βarr1 in modulating AR signaling to regulate prostate cancer aggressiveness is cell and host autonomous.

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Hyperlipidic Diet-induced Obesity Increased Proliferative Signals- AR, ERK1/2- on Mice Prostate, Which can be Restored through Physical Training

Advances in Research ◽

10.9734/air/2020/v21i1130272 ◽

2020 ◽

pp. 79-90

Author(s):

João Vitor Pereira Leite ◽

Daniela Cristina de Cario Calaça ◽

Pedro Augusto Silva Nogueira ◽

Renata Graciele Zanon ◽

Daniele Lisboa Ribeiro

Keyword(s):

Cell Proliferation ◽

Physical Exercise ◽

Caspase 3 ◽

Saturated Fat ◽

Nuclear Antigen ◽

Diet Induced Obesity ◽

Mouse Prostate ◽

Hyperlipidic Diet ◽

Fat Uptake ◽

Proliferating Cell

Aims: To evaluate the effects of hyperlipidic diet on the mouse prostate and also investigate if physical exercise is able to restore such effects. Methodology: Adult male Swiss mice were fed with a balanced (ND) or hyperlipidic diet (45% saturated fat, HD) for 16 weeks. Half were submitted to a sedentary (NDS and HDS) or exercise routine (swimming- NDE and HDE) for 8 weeks. Then, the prostate was analyzed by immunoreactions (proliferating cell nuclear antigen- PCNA, androgen receptor- AR, and estrogen receptor-ERβ), western blotting (ERK 1/2), and caspase-3 activity. Results: We found that saturated fat uptake promoted 16% weight gain, increased fat-mass and hyperglycaemia, as well as reduced testosterone levels. In addition, HD atrophied prostate secretory epithelium and stimulated cell proliferation through higher expression of AR and activation of ERK signaling. Additionally, saturated fat reduced prostatic ERβ content. Physical exercise per se promoted an anabolic effect by increasing testosterone and stimulating cell proliferation in the prostate of sedentary animals. Finally, exercise was able to restore the proliferative signals caused by the hyperlipidic diet on prostate. Conclusion: We suggest that the combination of hyperlipidic diet and sedentary lifestyle could negatively affected some prostate stimulating pathways that could trigger proliferative diseases in mice and physical exercise may be an interesting strategy to reverse such effects.

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Targeted Biallelic Inactivation of Pten in the Mouse Prostate Leads to Prostate Cancer Accompanied by Increased Epithelial Cell Proliferation but not by Reduced Apoptosis

Cancer Research ◽

10.1158/0008-5472.can-04-4519 ◽

2005 ◽

Vol 65 (13) ◽

pp. 5730-5739 ◽

Cited By ~ 140

Author(s):

Xiaoqian Ma ◽

Angelique C. Ziel-van der Made ◽

Binha Autar ◽

Hetty A. van der Korput ◽

Marcel Vermeij ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Epithelial Cell ◽

Epithelial Cell Proliferation ◽

Mouse Prostate

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Intra-epithelial non-canonical Activin A signalling safeguards prostate progenitor quiescence

10.1101/2021.03.05.433921 ◽

2021 ◽

Author(s):

Francesco Cambuli ◽

Veronica Foletto ◽

Alessandro Alaimo ◽

Dario De Felice ◽

Francesco Gandolfi ◽

...

Keyword(s):

Activin A ◽

Quiescent State ◽

Independent Manner ◽

Mapk Activity ◽

Mouse Prostate ◽

Cancer Initiation ◽

Dna Replication Stress ◽

Immunocompetent Mice ◽

Prostate Epithelium

AbstractThe healthy prostate is a relatively quiescent tissue. Yet, prostate epithelium overgrowth is a common condition during ageing, associated with urinary dysfunction and tumorigenesis. For over thirty years, TGF-β ligands have been known to induce cytostasis in a large variety of epithelia, but the intracellular pathway mediating this signal in the prostate, as well as its relevance for quiescence, have remained elusive.Here, using mouse prostate organoids to model epithelial progenitors, we found that intra-epithelial non-canonical Activin A signalling inhibited cell proliferation in a Smad-independent manner. Mechanistically, Activin A triggered Tak1 and p38 MAPK activity, leading to p16 and p21 nuclear import. Spontaneous evasion from this quiescent state occurred upon prolonged culture, due to reduced Activin A secretion, a condition associated with DNA replication stress and aneuploidy. Organoids capable to escape quiescence in vitro were also able to implant with increased frequency into immunocompetent mice.Our study demonstrates that non-canonical Activin A signalling safeguards epithelial quiescence in the healthy prostate, with potential implications for the understanding of cancer initiation, and the development of therapies targeting quiescent tumour progenitors.

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Bioactive tomato components inhibit cancer promoting activity of testosterone in the mouse prostate epithelium

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.1023.4 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Hsueh-Li Tan ◽

Amy C. Elsen ◽

John W. Erdman ◽

Jennifer M. Thomas-Ahner ◽

Steven K. Clinton

Keyword(s):

Mouse Prostate ◽

Prostate Epithelium

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