The expression of androgen‐responsive genes is Up‐Regulated in the epithelia of benign prostatic hyperplasia

O’Malley, Katherine J.; Dhir, Rajiv; Nelson, Joel B.; Bost, James E.; Lin, Yangyang; Wang, Zhou

doi:10.1002/pros.21034

Cited by 45 publications

(46 citation statements)

References 38 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In BPH-1 human prostate epithelial cells and WPMY-1 normal prostate stromal cells, the expression of GRP-R was confirmed by RT-PCR, immunofluorescent microscopy, and ligand competition assay. Androgen signaling is significantly elevated in BPH relative to the normal prostate (33). In addition, prostate epithelial AR function seems to be important for macrophage-mediated epithelial-mesenchymal transition and proliferation of prostate epithelial cells (34).…”

Section: Discussionmentioning

confidence: 99%

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Rick

Abi-Chaker

Szalontay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Gastrin releasing-peptide (GRP) is a potent growth factor in many malignancies. Benign prostatic hyperplasia (BPH) is a progressive age-related proliferation of glandular and stromal tissues; various growth factors and inflammatory processes are involved in its pathogenesis. We have demonstrated that potent antagonists of GRP inhibit growth of experimental human tumors including prostate cancer, but their effect on models of BPH has not been studied. Here, we evaluated the effects of GRP antagonist RC-3940-II on viability and cell volume of BPH-1 human prostate epithelial cells and WPMY-1 prostate stromal cells in vitro, and in testosterone-induced BPH in Wistar rats in vivo. RC-3940-II inhibited the proliferation of BPH-1 and WPMY-1 cells in a dosedependent manner and reduced prostatic cell volume in vitro. Shrinkage of prostates was observed after 6 wk of treatment with RC-3940-II: a 15.9% decline with 25 μg/d; and a 18.4% reduction with 50 μg/d (P < 0.05 for all). Significant reduction in levels of proliferating cell nuclear antigen, NF-κβ/p50, cyclooxygenase-2, and androgen receptor was also seen. Analysis of transcript levels of genes related to growth, inflammatory processes, and signal transduction showed significant changes in the expression of more than 90 genes (P < 0.05). In conclusion, GRP antagonists reduce volume of human prostatic cells and lower prostate weight in experimental BPH through direct inhibitory effects on prostatic GRP receptors. GRP antagonists should be considered for further development as therapy for BPH.bombesin | cell volume measurement | prostatic inflammation | rodent benign prostatic hyperplasia model | targeted therapy H ormonal polypeptides, bombesin (BN) and gastrin-releasing peptide (GRP), can act as autocrine and paracrine growth factors, and regulate cellular growth, differentiation, and apoptosis (1, 2). Tetradecapeptide bombesin was isolated from the skin of the European fire-bellied toad (Bombina bombina) (3), and subsequently, two mammalian bombesin-like peptides were characterized: GRP and neuromedin B (NMB) (4). GRP and BN influence the secretion of gastrointestinal hormones, stimulate the release of gastrin and somatostatin, induce pancreatic exocrine secretion (5), and induce contractions of the smooth muscle of the stomach, gall bladder, uterus, urinary bladder, and prostate (6). GRP was first shown to be a mitogen for Swiss 3T3 murine embryonal fibroblasts and, subsequently, for a number of normal cell types and cancers in vivo and in cell culture (7). GRP is now recognized as the prototypical autocrine growth factor, based on the detection of GRP and its receptors in small cell lung carcinoma and other tumors (8). GRP was shown to stimulate growth of several other types of carcinomas including those of prostate, breast, colon, and pancreas (9). Three different receptor subtypes for the BN/GRP family of peptides have been described in mammals (10). Receptor subtype 1 (termed GRP-R or BB 2 ) binds BN, GRP, and GRP antagonist RC-3940-II with high affinity (11). ...

show abstract

Section: Discussionmentioning

confidence: 99%

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Rick

Abi-Chaker

Szalontay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Reverse Transcription and Real-time PCR-We used TRIzol reagent to isolate total RNA from either worm tissues or human cells, and 1 g of total RNA was subjected to reverse transcription, followed by real-time PCR as described previously (28). Primer information is provided in supplemental Table 2.…”

Section: Methodsmentioning

confidence: 99%

Regulation of Fertility, Survival, and Cuticle Collagen Function by the Caenorhabditis elegans eaf-1 and ell-1 Genes

Cai

Phong

Fisher

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

EAF2, an androgen-regulated protein, interacts with members of the ELL (eleven-nineteen lysine-rich leukemia) transcription factor family and also acts as a tumor suppressor. Although these proteins control transcriptional elongation and perhaps modulate the effects of other transcription factors, the mechanisms of their actions remain largely unknown. To gain new insights into the biology of the EAF2 and ELL family proteins, we used Caenorhabditis elegans as a model to explore the in vivo roles of their worm orthologs. Through the use of transgenic worms, RNAi, and an eaf-1 mutant, we found that both genes are expressed in multiple cell types throughout the worm life cycle and that they play important roles in fertility, survival, and body size regulation. ELL-1 and EAF-1 likely contribute to these activities in part through modulating cuticle synthesis, given that we observed a disrupted cuticle structure in ell-1 RNAi-treated or eaf-1 mutant worms. Consistent with disruption of cuticle structure, loss of either ELL-1 or EAF-1 suppressed the rol phenotype of specific collagen mutants, possibly through the control of dpy-3, dpy-13, and sqt-3 collagen gene expression. Furthermore, we also noted the regulation of collagen expression by ELL overexpression in PC3 human prostate cancer cells. Together, these results reveal important roles for the eaf-1 and ell-1 genes in the regulation of extracellular matrix components.Androgens play a key role in prostate development, prostate cancer, and benign prostatic hyperplasia. Thus, identification and characterization of androgen-responsive genes could significantly contribute to the prevention and treatment of prostate cancer and benign prostatic hyperplasia. One such androgen-responsive gene is EAF2 (ELL-associated factor 2), which may serve as a tumor suppressor (1). The EAF2 locus exhibits frequent allelic loss in ϳ80% of advanced clinical prostate cancer specimens, and evidence for homozygous deletion also exists (1). EAF2 deficiency in mice leads to carcinogenesis in multiple tissues (2) as well as aspermatogenesis and reduced survival (3). In addition to EAF2, mammals also express EAF1, a protein that shares 58% identity and 74% similarity with EAF2. Both EAF proteins interact with the ELL family of transcription elongation factors, including ELL, ELL2, and ELL3 (4 -9). ELL has been identified in an array of species, including yeast (10), Drosophila (11), zebrafish (12), mouse (13), and human (14). This widely expressed gene is essential for embryonic development because deletion of ELL in mouse or Drosophila causes embryonic lethality (15,16). ELL also plays an important role in leukemia (8,17). Chromosomal translocation can lead to fusion of ELL with the MLL (multiple lineage leukemia) gene, and the MLL-ELL fusion protein can cause acute myeloid leukemia (8,18).The mechanisms of EAF/ELL action appear to be complex and involve multiple signaling pathways. ELL family proteins interact with RNA polymerase II and act as a transcription elongation factor (4, 19). Eisse...

show abstract

“…Since high expression of ELL2 has been reported in the prostate (Uhlen, et al 2005), ELL2 may be important for prostate homeostasis. ELL2 was also found to be an androgen response gene (Nelson, et al 2002; Bolton, et al 2007) that is up-regulated in response to chronic prostatic inflammation in rats (Funahashi, et al 2015) and was up-regulated in human benign prostatic hyperplasia (BPH) (O’Malley, et al 2009). The specific role of ELL2 in the prostate has not been fully elucidated; however, transfected ELL2 protein has been shown to interact with the potential prostate tumor suppressor gene ELL-associated factor 2 (EAF2) (Simone et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

Pascal

Masoodi

Liu

et al. 2017

Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

Elongation factor, RNA polymerase II, 2 (ELL2) is an RNA Pol II elongation factor with functional properties similar to ELL that can interact with the prostate tumor suppressor EAF2. In the prostate, ELL2 is an androgen response gene that is up-regulated in benign prostatic hyperplasia (BPH). We recently showed that ELL2 loss could enhance prostate cancer cell proliferation and migration, and that ELL2 gene expression was down-regulated in high Gleason score prostate cancer specimens. Here, prostate-specific deletion of ELL2 in a mouse model revealed a potential role for ELL2 as a prostate tumor suppressor in vivo. Ell2 knockout mice exhibited prostatic defects including increased epithelial proliferation, vascularity and PIN lesions similar to the previously determined prostate phenotype in Eaf2 knockout mice. Microarray analysis of prostates from Ell2 knockout and wild-type mice on a C57BL/6J background at age 3 mos and qPCR validation at 17 mos of age revealed a number of differentially expressed genes associated with proliferation, cellular motility and epithelial and neural differentiation. OncoPrint analysis identified combined down-regulation or deletion in prostate adenocarcinoma cases from the Cancer Genome Atlas (TCGA) data portal. These results suggest that ELL2 and its pathway genes likely play an important role in the development and progression of prostate cancer.

show abstract

The expression of androgen‐responsive genes is Up‐Regulated in the epithelia of benign prostatic hyperplasia

Cited by 45 publications

References 38 publications

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Regulation of Fertility, Survival, and Cuticle Collagen Function by the Caenorhabditis elegans eaf-1 and ell-1 Genes

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

Contact Info

Product

Resources

About