scholarly journals Recruitment of β-Catenin by Wild-Type or Mutant Androgen Receptors Correlates with Ligand-Stimulated Growth of Prostate Cancer Cells

2004 ◽  
Vol 18 (10) ◽  
pp. 2388-2401 ◽  
Author(s):  
David Masiello ◽  
Shao-Yong Chen ◽  
Youyuan Xu ◽  
Manon C. Verhoeven ◽  
Eunis Choi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Nuclear Receptor ◽  
Specific Antigen ◽  
Prostate Cancer Cells ◽  
Prostate Cell ◽  
Nuclear Receptor Corepressor ◽  
Prostate Cancers

Abstract Prostate cancers respond to treatments that suppress androgen receptor (AR) function, with bicalutamide, flutamide, and cyproterone acetate (CPA) being AR antagonists in clinical use. As CPA has substantial agonist activity, it was examined to identify AR coactivator/corepressor interactions that may mediate androgen-stimulated prostate cancer growth. The CPA-liganded AR was coactivated by steroid receptor coactivator-1 (SRC-1) but did not mediate N-C terminal interactions or recruit β-catenin, indicating a nonagonist conformation. Nonetheless, CPA did not enhance AR interaction with nuclear receptor corepressor, whereas the AR antagonist RU486 (mifepristone) strongly stimulated AR-nuclear receptor corepressor binding. The role of coactivators was further assessed with a T877A AR mutation, found in LNCaP prostate cancer cells, which converts hydroxyflutamide (HF, the active flutamide metabolite) into an agonist that stimulates LNCaP cell growth. The HF and CPA-liganded T877A ARs were coactivated by SRC-1, but only the HF-liganded T877A AR was coactivated by β-catenin. L-39, a novel AR antagonist that transcriptionally activates the T877A AR, but still inhibits LNCaP growth, similarly mediated recruitment of SRC-1 and not β-catenin. In contrast, β-catenin coactivated a bicalutamide-responsive mutant AR (W741C) isolated from a bicalutamide-stimulated LNCaP subline, further implicating β-catenin recruitment in AR-stimulated growth. Androgen-stimulated prostate-specific antigen gene expression in LNCaP cells could be modulated by β-catenin, and endogenous c-myc expression was repressed by dihydrotestosterone, but not CPA. These results indicate that interactions between AR and β-catenin contribute to prostate cell growth in vivo, although specific growth promoting genes positively regulated by AR recruitment of β-catenin remain to be identified.

scholarly journals Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Denisa Baci ◽  
Antonino Bruno ◽  
Caterina Cascini ◽  
Matteo Gallazzi ◽  
Lorenzo Mortara ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Dietary Supplements ◽  
Cell Lines ◽  
Angiogenic Factors ◽  
Migration And Invasion ◽  
Prostate Cancer Cells

Abstract Background Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. Methods The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. Results We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. Conclusions Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible “repurposed agent’ for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.

Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16534-e16534 ◽  
Author(s):  
Lisa Butler ◽  
Swati Irani ◽  
Margaret Centenera ◽  
Natalie Ryan ◽  
Neil Pegg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Single Agent ◽  
Specific Antigen ◽  
Resistance Mechanisms ◽  
Prostate Cancer Cells ◽  
In Vivo Models

e16534 Background: Growth and survival of prostate cancer cells are initially dependent upon androgens, and androgen deprivation therapy (ADT) is used to control tumor growth. Unfortunately, resistance to ADT inevitably occurs, and patients relapse with lethal castrate-resistant prostate cancer (CRPC). Increased expression of the androgen receptor (AR) and constitutively active AR variants are hallmarks of CRPC, and treatments targeting aberrant AR signaling are urgently required. CCS1477 is an inhibitor of p300/CBP currently in a Phase I/IIa study for CRPC. CCS1477 enhances degradation of numerous cellular proteins including the AR and AR variants in prostate cancer cells. Our preclinical studies with this compound demonstrated potent single-agent efficacy of CCS1477 using in vitro and in vivo models of prostate cancer and, when used in combination, CCS1477 enhances the efficacy of enzalutamide, a clinical AR antagonist. Understanding the response of clinical tumors to CCS1477, and their potential adaptive evolution, is essential to personalize treatment and predict potential resistance mechanisms. Methods: To assess CCS1477 in human disease, we used a unique model in which clinical prostate tumors from radical prostatectomy are cultured as explants with maintenance of tissue integrity, cell proliferation and androgen signaling. Tumors from 13 patients were cultured in the absence or presence of CCS1477 (10µM) or enzalutamide (10µM) for 48 or 72 hours; micromolar doses were selected to account for altered small molecule uptake and penetration into tissues compared to cell lines, as previously reported. Proliferation, apoptosis and androgen signaling were all analyzed post-culture. Results: Whereas the tumor explants exhibited highly heterogenous proliferative responses to enzalutamide, tumors from all patients exhibited a marked antiproliferative response to CCS1477 (mean reduction in Ki67 immunoreactivity of > 90% compared to vehicle control; p < 0.0005). Culture with CCS1477 was associated with repression of androgen signaling in the prostate tissues, measured by expression and secretion of the clinical biomarker prostate specific antigen (PSA). Conclusions: The consistent and pronounced efficacy of CCS1477 in this patient-derived model would support further investigation of this class of epigenetic agents in the castrate-sensitive prostate cancer setting.

Prostate-specific antigen (PSA) protein does not affect growth of prostate cancer cells in vitro or prostate cancer xenografts in vivo

The Prostate ◽  
2003 ◽  
Vol 56 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Samuel R. Denmeade ◽  
Ivan Litvinov ◽  
Lori J. Sokoll ◽  
Hans Lilja ◽  
John T. Isaacs
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Prostate Cancer Cells

scholarly journals Human Checkpoint Protein hRad9 Functions as a Negative Coregulator To Repress Androgen Receptor Transactivation in Prostate Cancer Cells

2004 ◽  
Vol 24 (5) ◽  
pp. 2202-2213 ◽  
Author(s):  
Liang Wang ◽  
Cheng-Lung Hsu ◽  
Jing Ni ◽  
Peng-Hui Wang ◽  
Shuyuan Yeh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Specific Antigen ◽  
Luciferase Reporter ◽  
Signal Pathways ◽  
Prostate Cancer Cells ◽  
C Terminus ◽  
Two Hybrid

ABSTRACT Positive responses to combined androgen elimination therapy and radiation therapy have been well documented in the treatment of prostate cancer patients. The detailed mechanisms how androgen-androgen receptor (AR) cross talks to the radiation-related signal pathways, however, remain largely unknown. Here we report the identification of hRad9, a key member of the checkpoint Rad protein family, as a coregulator to suppress androgen-AR transactivation in prostate cancer cells. In vivo and in vitro interaction assays using Saccharomyces cerevisiae two-hybrid, mammalian two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation methods prove that AR can interact with the C terminus of hRad9 via its ligand binding domain. The FXXLF motif within the C terminus of hRad9 interrupts the androgen-induced interaction between the N terminus and C terminus of AR. This interaction between AR and hRad9 may result in the suppression of AR transactivation, demonstrated by the repressed AR transactivation in androgen-induced luciferase reporter assay and the reduced endogenous prostate-specific antigen expression in Western blot assay. Addition of small interfering RNA of hRad9 can reverse hRad9 suppression effects, which suggests that hRad9 functions as a repressor of AR transactivation in vivo. Together, our data provide the first linkage between androgen-AR signals and radiation-induced responses. Further studies of the influence of hRad9 on prostate cancer growth may provide potential new therapeutic approaches.

Exercise alters the IGF axis in vivo and increases p53 protein in prostate tumor cells in vitro

2004 ◽  
Vol 96 (2) ◽  
pp. 450-454 ◽  
Author(s):  
Pak-Shan Leung ◽  
William J. Aronson ◽  
Tung H. Ngo ◽  
Lawrence A. Golding ◽  
R. James Barnard
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
P53 Protein ◽  
Nuclear Antigen ◽  
Prostate Cancer Cells ◽  
Serum Factors ◽  
Control Serum

Epidemiological studies report that regular physical activity can reduce the risk for prostate cancer, the most common solid-tumor cancer in US men. Regular exercise alters the serum IGF axis in vivo and reduces cell proliferation while increasing apoptosis in serum-stimulated LNCaP prostate cancer cells in vitro. The present study tests the hypothesis that these effects on tumor cell lines are mediated by enhancement of the function of the p53 gene known to arrest cell growth and induce apoptosis. When LNCaP cells were cultured in exercise serum and compared with control serum, cell growth was reduced by 27%, and there was a similar 33% decrease in proliferating cell nuclear antigen protein, a marker for cell cycling. Apoptosis was increased by 371% with the exercise serum, and there was a 100% increase in p53 protein (75.2 ± 2.0 vs. 38.2 ± 2.0 pg/μg protein). When serum was used to stimulate LN-56 cells, a cell line with nonfunctional p53 derived from LNCaP, no significant reduction in cell growth or increase in apoptosis with the exercise serum was observed. These results indicate that exercise training alters serum factors in vivo that increase cellular p53 protein content and is associated with reduced growth and induced apoptosis in LNCaP prostate cancer cells in vitro.

Pinin promotes tumor progression via PI3K/AKT/CREB signaling pathway in prostate cancer

2020 ◽  
Author(s):  
Xiang-yu Meng ◽  
Hui-zhi Zhang ◽  
Yi-yue Ren ◽  
Ke-jie Wang ◽  
Jun-feng Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Western Blotting ◽  
Cell Invasion ◽  
Tumor Stage ◽  
Prostate Cancer Cells ◽  
Mechanism Study

Abstract Background Pinin (PNN), a desmosome associated protein, was demonstrated to be over-expressed and act as a tumor-promoting factor in ovarian cancer, hepatocellular carcinoma and colorectal cancer. However, the precise role of PNN in prostate cancer is still unknown. Methods The expression levels of PNN were assessed in prostate cancer by qRT-PCR, western blotting and immunohistochemical staining. The other proteins were quantified by western blotting. PNN-depleted cells were produced by infecting with lentivirus bearing short hairpin RNAs against PNN. PNN over-expression was performed by transfecting PNN expression vector. The proliferation of each cell line was assessed by MTS and colony formation assays. Tumors were induced on nude mice by injecting tumor cells subcutaneously. Apoptosis and cell cycle were evaluated by flow cytometry. Transwell and wound healing assay were performed to determined the ability of cell invasion and migration. The TCGA data were analyzed with GEPIA (Gene Expression Profiling Interactive Analysis) and GraphPad Prism. Results Here, we reported that PNN was upregulated in prostate cancer tissues and PNN expression was positively associated with Gleason score, tumor stage and tumor metastasis. PNN promoted cell growth and tumorigenicity in vitro and in vivo, and might modulate cell growth through driving G1/S transition via CDK6, CDK2, and Cyclin D1 in prostate cancer cells. Furthermore, PNN accelerated cell invasion, migration and EMT processes of prostate cancer cells accompanied with the up-regulation of MMP-2, MMP-9, N-cadherin, Vimentin and down-regulation of E-cadherin. Mechanism study demonstrated that the proliferation- and motility-promoting effects of PNN on prostate cancer cells dependent on the activation of PI3K/AKT/CREB signaling, which was reversed by AKT and CREB inhibitors. Conclusions Collectively, these findings indicated that PNN plays important roles in prostate cancer tumorigenesis and progression and it may be a potential therapeutic target for prostate cancer treatment.

scholarly journals PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells

2010 ◽  
Vol 32 (1-2) ◽  
pp. 11-27
Author(s):  
Mari Kaarbø ◽  
Øyvind Løveseter Mikkelsen ◽  
Lene Malerød ◽  
Su Qu ◽  
Viola H. Lobert ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Pi3k Pathway ◽  
Prostate Cancer Cells ◽  
Pathway Inhibition

Background: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechanisms are not clear. Here we studied the AR–PI3K pathway crosstalk in prostate cancer cells in vitro as well as in vivo.Methods: Quantitative PCR, Western analysis, reporter assays, and proliferation analyses in vitro and in vivo were used to evaluate the effect of PI3K pathway inhibition on AR signaling and cell growth.Results: Transcriptional activity of AR was increased when the PI3K pathway was inhibited at different levels. In the androgen responsive prostate cancer cell line LNCaP, androgen and the mTOR inhibitor rapamycin synergistically activated androgen target genes. Despite increased androgen signaling, rapamycin treatment reduced LNCaP cell growth; the AR antagonist bicalutamide potentiated this effect. Furthermore, the rapamycin derivative CCI-779 reduced the growth of CWR22 prostate cancer xenografts while increasing AR target gene expression.Conclusions: These findings suggest that inhibition of the PI3K pathway activates AR signaling. Despite the increase in AR signaling which has proliferative effects, the result of PI3K pathway inhibition is antiproliferative. These findings suggest that the PI3K pathway is dominant over AR signaling in prostate cancer cells which should be considered in developing novel therapeutic strategies for prostate cancer.

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