scholarly journals Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer

2015 ◽  
Vol 23 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Jan Kroon ◽  
Martin Puhr ◽  
Jeroen T Buijs ◽  
Geertje van der Horst ◽  
Daniëlle M Hemmer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Glucocorticoid Receptor ◽  
Cell Lines ◽  
Chemotherapy Resistance ◽  
Clinical Problem ◽  
Dependent Manner ◽  
Ru 486 ◽  
Docetaxel Resistance ◽  
Docetaxel Treatment

Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa.

scholarly journals Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis

2006 ◽  
Vol 203 (1) ◽  
pp. 189-201 ◽  
Author(s):  
Ronit Vogt Sionov ◽  
Orly Cohen ◽  
Shlomit Kfir ◽  
Yael Zilberman ◽  
Eitan Yefenof
Keyword(s):  
T Cell ◽  
Glucocorticoid Receptor ◽  
Cell Lines ◽  
Cell Types ◽  
Thymic Epithelial Cells ◽  
Dependent Manner ◽  
Localization Signal ◽  
Induced Apoptosis ◽  
T Cell Lines

The mechanisms by which glucocorticoid receptor (GR) mediates glucocorticoid (GC)-induced apoptosis are unknown. We studied the role of mitochondrial GR in this process. Dexamethasone induces GR translocation to the mitochondria in GC-sensitive, but not in GC-resistant, T cell lines. In contrast, nuclear GR translocation occurs in all cell types. Thymic epithelial cells, which cause apoptosis of the PD1.6 T cell line in a GR-dependent manner, induce GR translocation to the mitochondria, but not to the nucleus, suggesting a role for mitochondrial GR in eliciting apoptosis. This hypothesis is corroborated by the finding that a GR variant exclusively expressed in the mitochondria elicits apoptosis of several cancer cell lines. A putative mitochondrial localization signal was defined to amino acids 558–580 of human GR, which lies within the NH2-terminal part of the ligand-binding domain. Altogether, our data show that mitochondrial and nuclear translocations of GR are differentially regulated, and that mitochondrial GR translocation correlates with susceptibility to GC-induced apoptosis.

scholarly journals Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Qing Shi ◽  
Yasheng Zhu ◽  
Jian Ma ◽  
Kun Chang ◽  
Dongling Ding ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Hybrid Methods ◽  
Biological Significance ◽  
Therapy Resistance ◽  
Dependent Manner ◽  
Gene Encoding ◽  
Docetaxel Resistance ◽  
Cancer Pathogenesis

Abstract Background The gene encoding the E3 ubiquitin ligase substrate-binding adaptor SPOP is frequently mutated in primary prostate cancer, but how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. Stress granules (SG) assembly is an evolutionarily conserved strategy for survival of cells under stress, and often upregulated in human cancers. We investigated the role of SPOP mutations in aberrant activation of the SG in prostate cancer and explored the relevanve of the mechanism in therapy resistance. Methods We identified SG nucleating protein Caprin1 as a SPOP interactor by using the yeast two hybrid methods. A series of functional analyses in cell lines, patient samples, and xenograft models were performed to investigate the biological significance and clinical relevance of SPOP regulation of SG signaling in prostate cancer. Results The cytoplasmic form of wild-type (WT) SPOP recognizes and triggers ubiquitin-dependent degradation of Caprin1. Caprin1 abundance is elevated in SPOP-mutant expressing prostate cancer cell lines and patient specimens. SPOP WT suppresses SG assembly, while the prostate cancer-associated mutants enhance SG assembly in a Caprin1-dependent manner. Knockout of SPOP or expression of prostate cancer-associated SPOP mutants conferred resistance to death caused by SG inducers (e.g. docetaxel, sodium arsenite and H2O2) in prostate cancer cells. Conclusions SG assembly is aberrantly elevated in SPOP-mutated prostate cancer. SPOP mutations cause resistance to cellular stress induced by chemtherapeutic drug such as docetaxel in prostate cancer.

scholarly journals The role of microRNA-572 in the proliferation and chemotherapeutic treatment of prostate cancer

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110143
Author(s):  
Mingcui Zang ◽  
Xun Guo ◽  
Manqiu Chen
Keyword(s):  
Prostate Cancer ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Prostate Tumorigenesis ◽  
Expression Levels ◽  
Matrigel Invasion ◽  
Tensin Homolog ◽  
Docetaxel Treatment ◽  
Induced Apoptosis

Objective MicroRNAs (miRNAs) regulate prostate tumorigenesis and progression by involving different molecular pathways. In this study, we examined the role of miR-572 in prostate cancer (PCa). Methods The proliferation rates of LNCaP and PC-3 PCa cells were studied using MTT assays. Transwell migration and Matrigel invasion assays were performed to evaluate cell migration and invasion, respectively. Protein expression levels were examined using western blotting. Docetaxel-induced apoptosis was evaluated by Caspase-Glo3/7 assays. The putative miR-572 binding site in the phosphatase and tensin homolog (PTEN) 3ʹ untranslated region (3ʹ UTR) was assessed with dual-luciferase reporter assays. Additionally, miR-572 expression levels in human PCa tissues were examined by qRT-PCR assays. Results Upregulation of miR-572 promoted proliferation, migration, and invasion of PCa cells. Overexpression of miR-572 decreased sensitivity of PCa cells to docetaxel treatment by reducing docetaxel-induced apoptosis. MiR-572 can regulate migration and invasion in PCa cells. Furthermore, miR-572 could regulate expression of PTEN and p-AKT in PCa cells by directly binding to the PTEN 3ʹ UTR. MiR-572 expression levels were increased in human PCa tissues and associated with PCa stage. Conclusions miR-572 displayed essential roles in PCa tumor growth and its expression level may be used to predict docetaxel treatment in these tumors.

scholarly journals IL6 sensitizes prostate cancer to the antiproliferative effect of IFNα2 through IRF9

2013 ◽  
Vol 20 (5) ◽  
pp. 677-689 ◽  
Author(s):  
Holger H H Erb ◽  
Regina V Langlechner ◽  
Patrizia L Moser ◽  
Florian Handle ◽  
Tineke Casneuf ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Tissue Expression ◽  
Type I ◽  
Regulatory Factor ◽  
Quantitative Real Time Pcr ◽  
Antiproliferative Effects ◽  
Protein Levels

Development and progression of prostate cancer (PCa) are associated with chronic inflammation. The cytokine interleukin 6 (IL6) can influence progression, differentiation, survival, and angiogenesis of PCa. To identify novel pathways that are triggered by IL6, we performed a gene expression profiling of two PCa cell lines, LNCaP and MDA PCa 2b, treated with 5 ng/ml IL6. Interferon (IFN) regulatory factor 9 (IRF9) was identified as one of the most prevalent IL6-regulated genes in both cell lines. IRF9 is a mediator of type I IFN signaling and acts together with STAT1 and 2 to activate transcription of IFN-responsive genes. The IL6 regulation of IRF9 was confirmed at mRNA and protein levels by quantitative real-time PCR and western blot respectively in both cell lines and could be blocked by the anti-IL6 antibody Siltuximab. Three PCa cell lines, PC3, Du-145, and LNCaP-IL6+, with an autocrine IL6 loop displayed high expression of IRF9. A tissue microarray with 36 PCa tissues showed that IRF9 protein expression is moderately elevated in malignant areas and positively correlates with the tissue expression of IL6. Downregulation and overexpression of IRF9 provided evidence for an IFN-independent role of IRF9 in cellular proliferation of different PCa cell lines. Furthermore, expression of IRF9 was essential to mediate the antiproliferative effects of IFNα2. We concluded that IL6 is an inducer of IRF9 expression in PCa and a sensitizer for the antiproliferative effects of IFNα2.

scholarly journals Differential role of TRP channels in prostate cancer

2007 ◽  
Vol 35 (1) ◽  
pp. 133-135 ◽  
Author(s):  
N. Prevarskaya ◽  
M. Flourakis ◽  
G. Bidaux ◽  
S. Thebault ◽  
R. Skryma
Keyword(s):  
Prostate Cancer ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Clinical Problem ◽  
Tissue Growth ◽  
Transient Receptor Potential Channels ◽  
Potential Channels ◽  
Differentiation And Proliferation

A major clinical problem with PC (prostate cancer) is the cell's ability to survive and proliferate upon androgen withdrawal. Indeed, deregulated cell differentiation and proliferation, together with the suppression of apoptosis, provides the condition for abnormal tissue growth. Here, we examine the differential role of TRP (transient receptor potential) channels in the control of Ca2+ homoeostasis and growth of PC cells.

scholarly journals Effect of genetic variants in FAS and let-7a on radiation-induced intestinal toxicity in the treatment of prostate cancer

2021 ◽  
Author(s):  
Honglei Guo ◽  
Feng Yuan ◽  
Yancui Zhu ◽  
Ling He
Keyword(s):  
Prostate Cancer ◽  
Dependent Manner ◽  
Intestinal Toxicity ◽  
Rectal Volume ◽  
Obvious Association ◽  
Radiation Induced ◽  
Computational Analyses ◽  
Putative Marker ◽  
Dose Dependent

IntroductionThe present study aimed to explore the effects of pri-let-7a-1 rs10739971 and FAS-670 rs1800682 polymorphisms on the pathogenesis of radiation induced intestinal toxicity in prostate cancer (PC) patients.Material and methods380 PC patients with or without signs of intestinal toxicity were enrolled to study the effects of let-7a rs10739971 and FAS-670 rs1800682 polymorphisms on rectal volume and the risk of intestinal toxicity. In addition, real-time PCR, Western-blot analysis, immunohistochemistry, luciferase assays and computational analyses were performed to explore the mechanism underlying the role of let-7a rs10739971 polymorphism in radiation induced intestinal toxicity.ResultsThe let-7a rs10739971 polymorphism but not the FAS-670 rs1800682 polymorphism was closely related to the risk of radiation induced intestinal toxicity featured by a high rectal volume. In addition, there was no obvious association between the rectal volume and the genotype and allele frequencies of FAS -670 rs1800682 and Pri-let-7a-1 rs10739971 polymorphisms. The GG genotype of let-7a rs10739971 polymorphism reduced let-7a expression but enhanced FAS expression. In addition, the intestinal toxicity (-) group showed a much higher level of let-7a and a much lower level of FAS than the intestinal toxicity (+) group. FAS was a virtual target gene of let-7a, which decreased FAS protein expression in a dose-dependent manner.ConclusionsThe GG genotype of pri-let-7a-1 rs10739971 polymorphism could increase the risk of radiation induced intestinal toxicity in PC patients. Therefore, the pri-let-7a-1 rs10739971 polymorphism could be used as a putative marker to predict the risk of intestinal toxicity in PC patients undergoing radiotherapy.

scholarly journals Effect of Palmitic Acid on Exosome-Mediated Secretion and Invasive Motility in Prostate Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2722
Author(s):  
Ivan V. Maly ◽  
Wilma A. Hofmann
Keyword(s):  
Prostate Cancer ◽  
Palmitic Acid ◽  
Cancer Cells ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Concentration Dependent Manner ◽  
Fat Consumption ◽  
Progression Markers

High fat consumption can enhance metastasis and decrease survival in prostate cancer, but the picture remains incomplete on the epidemiological and cell-biological level, impeding progress toward individualized recommendations in the clinic. Recent work has highlighted the role of exosomes secreted by prostate cancer cells in the progression of the disease, particularly in metastatic invasion, and also the utility of targeting these extracellular vesicles for diagnostics, as carriers of disease progression markers. Here, we investigated the question of a potential impact of the chief nutritional saturated fatty acid on the exosome secretion. Palmitic acid decreased the secretion of exosomes in human prostate cancer cells in vitro in a concentration-dependent manner. At the same time, the content of some prospective metastatic markers in the secreted exosomal fraction was also reduced, as was the ability of the cells to invade across extracellular matrix barriers. While by themselves our in vitro results imply that on the cell level, palmitic acid may be beneficial vis-à-vis the course of the disease, they also suggest that, by virtue of the decreased biomarker secretion, palmitic acid has the potential to cause unjustified deprioritization of treatment in obese and lipidemic men.

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