ANDROGEN RECEPTOR CONVERTS FROM A GROWTH SUPPRESSOR IN THE NORMAL PROSTATE TO AN ONCOGENE IN PROSTATE CANCER

2011 ◽  
pp. 53-65
Author(s):  
Donald J. Vander Griend ◽  
John T. Isaacs
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Normal Prostate ◽  
Growth Suppressor

scholarly journals Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells

2021 ◽  
Vol 14 (2) ◽  
pp. 103
Author(s):  
Zohaib Rana ◽  
Joel D. A. Tyndall ◽  
Muhammad Hanif ◽  
Christian G. Hartinger ◽  
Rhonda J. Rosengren
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Hdac Inhibitors ◽  
G1 Arrest ◽  
Prostate Cancer Cells ◽  
Prostate Tumors ◽  
Normal Prostate ◽  
Pc3 Cells ◽  
Du145 Cells

Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.

scholarly journals The role of the androgen receptor as a driver and mitigator of cellular stress

2020 ◽  
Vol 65 (2) ◽  
pp. R19-R33
Author(s):  
Dimitrios Doultsinos ◽  
Ian Mills
Keyword(s):  
Prostate Cancer ◽  
Protein Synthesis ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Prostate Gland ◽  
Specific Antigen ◽  
Nuclear Hormone Receptor ◽  
Biological Processes ◽  
Normal Prostate ◽  
Mtor Activity

Prostate cancer is a high-incidence male cancer, which is dependent on the activity of a nuclear hormone receptor, the androgen receptor (AR). Since the AR is required for both normal prostate gland development and for prostate cancer progression, it is possible that prostate cancer evolves from perturbations in AR-dependent biological processes that sustain specialist glandular functions. The archetypal example of course is the use of prostate specific antigen (PSA), an organ-type specific component of the normal prostate secretome, as a biomarker of prostate cancer. Furthermore, localised prostate cancer is characterised by a low proliferative index and a heterogenous array of somatic mutations aligned to a multifocal disease pattern. We and others have identified a number of biological processes that are AR dependent and represent aberrations in significant glandular processes. Glands are characterised by high rates of metabolic activity including protein synthesis supported by co-dependent processes such as glycosylation, organelle biogenesis and vesicle trafficking. Impairments in anabolic metabolism and in protein folding/processing will inevitably impose proteotoxic and oxidative stress on glandular cells and, in particular, luminal epithelial cells for which secretion is their primary function. As cancer develops there is also significant metabolic dysregulation including impaired negative feedback effects on glycolytic and anabolic activity under conditions of hypoxia and heightened protein synthesis due to dysregulated PI 3-kinase/mTOR activity. In this review we will focus on the components of the AR regulome that support cancer development as well as glandular functions focussing on the unfolded protein response and on regulators of mTOR activity.

scholarly journals Metabolic Roles of Androgen Receptor and Tip60 in Androgen-Dependent Prostate Cancer

2020 ◽  
Vol 21 (18) ◽  
pp. 6622
Author(s):  
Kah Ni Tan ◽  
Vicky M. Avery ◽  
Catalina Carrasco-Pozo
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cell Fate ◽  
Tricarboxylic Acid Cycle ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Normal Prostate ◽  
Calcium Calmodulin Dependent ◽  
Metabolic Regulators

Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer.

Use of nuclear androgen receptor status to predict early biochemical recurrence of prostate cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21073-21073
Author(s):  
J. Diallo ◽  
A. Aldejmah ◽  
M. Alam Fahmy ◽  
I. Koumakpayi ◽  
A. Mes-Masson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Early Onset ◽  
Biochemical Recurrence ◽  
Normal Tissue ◽  
Cellular Localization ◽  
Nuclear Staining ◽  
Normal Prostate ◽  
Kaplan Meier ◽  
Hormone Sensitive

21073 Background: Prostate cancer (PCa) is a leading cause of cancer death in North American men. The androgen receptor (AR) has an established role in the progression of this disease; however, it is unclear at what stage it intervenes. It is also uncertain whether the AR can be a useful prognostic marker for PCa. In this study, we assessed AR expression and sub-cellular localization in normal prostate as well as in androgen sensitive and insensitive PCa (AIPCa) tissues, and evaluated the ability of the AR to predict biochemical recurrence (BCR). Methods: We used tissue micro-arrays containing prostate tissue cores obtained from cancer-free patients (n=43), AIPCa patients (n=36), and patients with hormone-sensitive cancers (n=64) from which were collected both cancerous and normal adjacent tissue. Using immmunohistochemistry, we stained the tissue micro-arrays with a monoclonal antibody recognizing the AR. Two observers assessed the frequency and intensity of both cytoplasmic and nuclear AR staining. AR cytoplasmic (Ci) and nuclear (Ni) indices were calculated by multiplying nuclear staining frequency and nuclear staining intensity. Kaplan Meier, and Cox multivariate analyses were done using SPSS. Results: We found that AR Ci increased significantly in AIPCa although a modest but significant increase in PCa Ci was observed compared to normal tissues. In contrast, AR Ni was significantly lower in cancer-free patients as opposed to that seen in normal tissue adjacent to cancer. Similarly, cancerous tissue exhibited higher AR Ni than its adjacent normal tissue (p<0.05, Kruskal-Wallis). Kaplan Meier analyses revealed that low AR Ni was predictive of an early onset of BCR (before 3-years) in the sub-cohort of hormone-sensitive patients (LR=6.51, p=0.011). Futhermore, low AR Ni remained an independent predictor of early BCR in a Cox multivariate model controlling for age, pre-operative PSA, lymph node invasion, Gleason score and surgical margin status (HR=2.28, 95% CI=1.04 - 5, p<0.05). Conclusions: We conclude that increased nuclear AR activity could be a pre-malignant step in PCa progression whereas its role within cancer cells may be more complex, as low AR nuclear activity was associated with early onset of BCR. No significant financial relationships to disclose.

Effect of the simultaneous blockade of androgen and estrogen receptors on prostate cancer: Preliminary results.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 168-168 ◽  
Author(s):  
R. Nunez-Nateras ◽  
E. P. Castle
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Synergistic Effect ◽  
Estrogen Receptors ◽  
Cell Lines ◽  
Simultaneous Administration ◽  
Normal Prostate ◽  
Androgen Receptor Antagonist ◽  
Receptor Modulator ◽  
Drug Concentrations

168 Background: Androgens and estrogens have been shown to play an important role in normal prostate development and function as well as carcinogenesis and development of the castration resistant phenotype of disease. The aim of this study was to evaluate the effect of a simultaneous administration of an androgen receptor antagonist (bicalutamide) and a selective estrogen receptor modulator (raloxifene) on both androgen sensitive and androgen insensitive prostate cancer cell lines. Methods: Experiments were performed on LNCaP, PC3 and DU145 cell lines. Western blot was utilized for the identification of androgen and estrogen receptors (a andb) in the cell lines. Drug concentrations required to achieve IC 50 were obtained using the MTT assay; such concentrations were identified for the drugs individually and when used in combination. The effect of the drugs on apoptosis was assessed using flow cytometry. Results: Results of the IC 50 for the drugs alone and in combination by each cell line are shown in the table. An enhanced effect was observed when the drugs were used in combination in all the cell lines. It was evident that the combination of the drugs decreased the total drug required to achieve the IC50 decreases considerably. Apoptosis rates were also affected by the simultaneous administration of bicalutamide and raloxifene. The synergistic effect of the combination was reflected in the increase of the apoptosis rate in all cell lines. Conclusions: The simultaneous administration of bicalutamide and raloxifene has a synergistic effect on cell death and apoptosis of DU145, PC3 and LNCaP cell lines. The pathway(s) responsible for this observation may be independent of the androgen receptor as both AR negative cell lines were still affected by the combination over the SERM alone. [Table: see text] No significant financial relationships to disclose.

scholarly journals The independent prognostic impact of the GATA2 pioneering factor is restricted to ERG-negative prostate cancer

Tumor Biology ◽  
2019 ◽  
Vol 41 (7) ◽  
pp. 101042831882481 ◽  
Author(s):  
Franziska Büscheck ◽  
Maciej Zub ◽  
Asmus Heumann ◽  
Claudia Hube-Magg ◽  
Ronald Simon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Progression ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Prognostic Impact ◽  
Gleason Grade ◽  
Advanced Tumor Stage ◽  
Normal Prostate ◽  
Advanced Tumor

GATA2 is a pioneering transcription factor governing androgen receptor expression and signaling in prostate cells. To understand the prognostic potential of GATA2 assessment in prostate cancer, we analyzed nuclear GATA2 expression on an annotated tissue microarray with 12,427 prostate cancer samples. Normal prostate glands were negative to weakly positive. GATA2 staining was found in almost all prostate cancers (95%). Strong GATA2 staining was linked to advanced tumor stage, high classical and quantitative Gleason grade (p < 0.0001 each), positive nodal stage (p = 0.0116), and early biochemical recurrence (p < 0.0001). GATA2 was linked to ERG-fusion-type cancers, with strong GATA2 staining in 29% of ERG-negative and 53% of ERG-positive cancers (p < 0.0001). Separate calculations in 3854 cancers with and 4768 cancers without TMPRSS2:ERG fusion revealed that these associations with tumor phenotype and patient outcome were largely driven by the subset of ERG-negative tumors. GATA2 expression was further linked to androgen receptor expression: Only 8% of androgen receptor-negative, but 56% of strongly androgen receptor expressing cancers had strong GATA2 expression (p < 0.0001). In conclusion, the results of our study demonstrate that increasing GATA2 levels are linked to prostate cancer progression and aggressiveness. The prognostic value of GATA2 is remarkable in ERG-negative cancers. However, the upregulation of GATA2 in ERG-positive cancers makes it unsuitable as a prognostic marker in this patient subset.

scholarly journals DNA licensing as a novel androgen receptor mediated therapeutic target for prostate cancer

2009 ◽  
Vol 16 (2) ◽  
pp. 325-332 ◽  
Author(s):  
Jason M D'Antonio ◽  
Donald J Vander Griend ◽  
John T Isaacs
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Dna Replication ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Prostate Cancer Cells ◽  
Normal Prostate ◽  
Malignant Prostate

During middle G1 of the cell cycle origins of replication orchestrate the ordered assembly of the pre-replication complex (pre-RC), allowing licensing of DNA required for DNA replication. Cyclin-dependent kinase activation of the pre-RC facilitates the recruitment of additional signaling factors, which triggers DNA unwinding and replication, while limiting such DNA replication to once and only once per cell cycle. For both the normal and malignant prostate, androgen is the major stimulator of cell proliferation and thus DNA replication. In both cases, the binding of androgen to the androgen receptor (AR) is required. However, the biochemical cascade involved in such AR-stimulated cell proliferation and DNA synthesis is dramatically different in normal versus malignant prostate cells. In normal prostate, AR-stimulated stromal cell paracrine secretion of andromedins stimulates DNA replication within prostatic epithelial cells, in which AR functions as a tumor suppressor gene by inducing proliferative quiescence and terminal differentiation. By direct contrast, nuclear AR in prostate cancer cells autonomously stimulates continuous growth via incorporation of AR into the pre-RC. Such a gain of function by AR-expressing prostate cancer cells requires that AR be efficiently degraded during mitosis since lack of such degradation leads to re-licensing problems, resulting in S-phase arrest during the subsequent cell cycle. Thus, acquisition of AR as part of the licensing complex for DNA replication represents a paradigm shift in how we view the role of AR in prostate cancer biology, and introduces a novel vulnerability in AR-expressing prostate cancer cells apt for therapeutic intervention.

scholarly journals Leupaxin, a Novel Coactivator of the Androgen Receptor, Is Expressed in Prostate Cancer and Plays a Role in Adhesion and Invasion of Prostate Carcinoma Cells

2008 ◽  
Vol 22 (7) ◽  
pp. 1606-1621 ◽  
Author(s):  
Silke Kaulfuss ◽  
Michal Grzmil ◽  
Bernhard Hemmerlein ◽  
Paul Thelen ◽  
Stefan Schweyer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Nuclear Export ◽  
Mutational Analysis ◽  
Specific Antigen ◽  
High Rate ◽  
Dependent Manner ◽  
Lncap Cells ◽  
Normal Prostate ◽  
Progression Marker

Abstract In the present study, we demonstrate that leupaxin mRNA is overexpressed in prostate cancer (PCa) as compared with normal prostate tissue by using cDNA arrays and quantitative RT-PCR analyses. Moderate to strong expression of leupaxin protein was detected in approximately 22% of the PCa tissue sections analyzed, and leupaxin expression intensities were found to be significantly correlated with Gleason patterns/scores. In addition, different leupaxin expression levels were observed in PCa cell lines, and at the subcellular level, leupaxin was usually localized in focal adhesion sites. Furthermore, mutational analysis and transfection experiments of LNCaP cells using different green fluorescent protein-leupaxin constructs demonstrated that leupaxin contains functional nuclear export signals in its LD3 and LD4 motifs, thus shuttling between the cytoplasm and the nucleus. We could also demonstrate for the first time that leupaxin interacts with the androgen receptor in a ligand-dependent manner and serves as a transcriptional activator of this hormone receptor in PCa cells. Down-regulation of leupaxin expression using RNA interference in LNCaP cells resulted in a high rate of morphological changes, detachment, spontaneous apoptosis, and a reduction of prostate-specific antigen secretion. In contrast, knockdown of leupaxin expression in androgen-independent PC-3 and DU 145 cells induced a significant decrease of both the invasive capacity and motility. Our results therefore indicate that leupaxin could serve as a potential progression marker for a subset of PCa and may represent a novel coactivator of the androgen receptor. Leupaxin could function as a putative target for therapeutic interventions of a subset of advanced PCa.

Sign in / Sign up

Export Citation Format

Share Document