Elevated circulating CCL2 in prostate cancer patients.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 201-201
Author(s):  
Justin Lin ◽  
Amanda Caress ◽  
Farzana Ahmed ◽  
Nicole Taylor ◽  
Yixuan Gong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Inflammatory Cytokines ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Dependent Manner ◽  
U937 Cells ◽  
Ccl2 Mrna ◽  
Pc3 Cells ◽  
Cytokine Array ◽  
Human Cytokine

201 Background: Monocyte chemoattractant protein 1 (CCL2 or MCP-1), a chemokine secreted by monocytic cells, is critical in recruiting Treg and MDSCs into the tumor microenvironment and in regulating prostate cancer (PCa) migration and proliferation. In this study, we examined circulating CCL2 levels in healthy vs PCa patients and used an in vitro coculture model to identify the source of the elevated CCL2. Methods: Serum CCL2 concentrations were evaluated via ELISA in 59 patients (19 health controls, 20 “treatment naïve” PCa, 20 mCRPC). Monocytic leukemia cells (U937) were either directly cocultured with PC3 PCa cell line or cultured in the PC3 conditioned medium (CM). The induction of CCL2 mRNA in the cultures was examined by qPCR. The secretion of CCL2 into cell culture supernatants was evaluated via human cytokine array. Neutralizing antibodies to several overexpressed inflammatory cytokines in PC3 cells were added into the PC3 CM to evaluate the contribution of these inflammatory cytokines to CCL2 induction. Results: Circulating CCL2 concentrations were significantly higher in prostate cancer patient serum compared to control patient serum (p=4.4e-6) (Table). To understand the potential source of elevated CCL2, we grew U937 and PC3 in coculture and evaluated with qPCR, revealing that while CCL2 was not expressed in PC3 cells, it was expressed at very low levels in U937 cells. Interestingly, coculture of PC3 with U937 increased CCL2 mRNA expression by over 10-fold, and the result was confirmed at protein levels by human cytokine array. Our results also indicated that IL-6 and GM-SCF were the two major cytokines released by PCa cells to induce CCL2 mRNA in U937 cells and MEK and JAK-STAT signaling were crucial for CCL2 induction. Conclusions: Prostate cancer cells induce CCL2 secretion from monocytes in an IL-6 and GM-CSF dependent manner. Given the critical role of CCL2 in mediating immunosuppressive tumor microenvironments, our study highlighted the CCL2 Concentrations in PCa vs Healthy Serum.[Table: see text]

scholarly journals HO-1 Interactors Involved in the Colonization of the Bone Niche: Role of ANXA2 in Prostate Cancer Progression

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 467 ◽  
Author(s):  
Nicolás Anselmino ◽  
Juan Bizzotto ◽  
Pablo Sanchis ◽  
Sofia Lage-Vickers ◽  
Emiliano Ortiz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Critical Role ◽  
Culture Conditions ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Annexin 2 ◽  
Raw264.7 Cell ◽  
Pc3 Cells

Background: Prostate cancer (PCa) dissemination shows a tendency to develop in the bone, where heme oxygenase 1 (HO-1) plays a critical role in bone remodeling. Previously by LC/ESI-MSMS, we screened for HO-1 interacting proteins and identified annexin 2 (ANXA2). The aim of this study was to analyze the relevance of ANXA2/HO-1 in PCa and bone metastasis. Methods: We assessed ANXA2 levels using a co-culture transwell system of PC3 cells (pre-treated or not with hemin, an HO-1 specific inducer) and the pre-osteoclastic Raw264.7 cell line. Results: Under co-culture conditions, ANXA2 mRNA levels were significantly modulated in both cell lines. Immunofluorescence analysis unveiled a clear ANXA2 reduction in cell membrane immunostaining for Raw264.7 under the same conditions. This effect was supported by the detection of a decrease in Ca2+ concentration in the conditioned medium. HO-1 induction in tumor cells prevented both, the ANXA2 intracellular relocation and the decrease in Ca2+ concentration. Further, secretome analysis revealed urokinase (uPA) as a key player in the communication between osteoclast progenitors and PC3 cells. To assess the clinical significance of ANXA2/HO-1, we performed a bioinformatics analysis and identified that low expression of each gene strongly associated with poor prognosis in PCa regardless of the clinico-pathological parameters assessed. Further, these genes appear to behave in a dependent manner. Conclusions: ANXA2/HO-1 rises as a critical axis in PCa.

scholarly journals MiR-657/ATF2 Signaling Pathway Has a Critical Role in Spatholobus suberectus Dunn Extract-Induced Apoptosis in U266 and U937 Cells

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 150 ◽  
Author(s):  
Hyun Lim ◽  
Moon Park ◽  
Changmin Kim ◽  
Beomku Kang ◽  
Hyo-Sook Song ◽  
...  
Keyword(s):  
Er Stress ◽  
Critical Role ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Parp Cleavage ◽  
Dependent Manner ◽  
U937 Cells ◽  
Anti Cancer ◽  
Spatholobus Suberectus ◽  
Induced Apoptosis ◽  
Related Proteins

Though Spatholobus suberectus Dunn (SSD) has been reported to have anti-virus, anti-osteoclastogenesis, and anti-inflammation activities, its underlying anti-cancer mechanism has never been elucidated in association with the role of miR-657 in endoplasmic reticulum (ER) stress-related apoptosis to date. SSD treatment exerted cytotoxicity in U266 and U937 cells in a dose-dependent manner. Also, apoptosis-related proteins such as PARP, procaspase-3, and Bax were regulated by SSD treatment. Furthermore, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that a number of apoptotic bodies were increased by SSD. Interestingly, the ER stress-related proteins such as p-ATF2 and CHOP were elevated by SSD. Interestingly, reactive oxygen species (ROS) generation and cytotoxicity by SSD treatment were significantly reduced by N-Acetyl-L-cysteine (NAC). Among the microRNAs (miRNAs) regulated by SSD treatment, miR-657 was most significantly reduced by SSD treatment. However, an miR-657 mimic reversed SSD-induced apoptosis by the attenuation of the expression of p-ATF2, CHOP, and PARP cleavage. Overall, these findings provide scientific evidence that miR657 is an onco-miRNA targeting the ER stress signal pathway and SSD induces apoptosis via the inhibition of miR-657, ROS, and the activation of p-ATF2 and CHOP as a potent anti-cancer agent for myeloid-originated hematological cancer.

scholarly journals ESTAT3 Inhibitor AG-490 Inhibits the Growth of Prostate Cancer by miR-503-5p Both In Vivo and In Vitro

2020 ◽  
Vol 19 ◽  
pp. 153303382094806
Author(s):  
Guangxing Tan ◽  
Lin Jiang ◽  
Gangqin Li ◽  
Kuan Bai
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Nude Mouse ◽  
Luciferase Reporter ◽  
Control Group ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Mouse Xenograft Model ◽  
Pc3 Cells ◽  
Du145 Cells

Objective: To explore the effect and the related mechanism of STAT3 inhibitor AG-490 on inhibiting the proliferation of prostate cancer cells. Methods: PC3 cells and DU145 cells were cultured stably and treated with AG-490 to detect the changes in the activity of PC3 cells and DU145 cells. Thirty 6-8 weeks male BALB/c nude mouse were randomly divided into a control group, a DMSO group, and an AG-490 group to detect differences in various indexes . Results: The overexpression of miR-503-5p depends on the activation of STAT3. After treatment with AG-490, The proliferation and invasion of PC3 cells and DU145 cells and the expression of miR-503-5p were all reduced. Luciferase reporter assay demonstrated that the target proteins of miR-503-5p include PDCD4, TIMP-3, and PTEN. After treatment with AG-490, the expression of PDCD4, TIMP-3, and PTEN in cells was significantly up-regulated. IL-6-induced overexpression of miR-503-5p and restored the expression of STAT3, demonstrating the correlation between STAT3 and miR-503-5p. AG-490 can inhibit tumor growth and induce tumor cell apoptosis in the PC3 BALB/c nude mouse xenograft model. Western blotting and immunohistochemical staining showed that the expression levels of STAT3, Ki67, Bcl-2 and MMP-2 in the AG-490 group were significantly reduced, and the expression of PDCD4, TIMP-3 and PTEN increased. Conclusion: AG-490 can inhibit the growth of prostate cancer cells in a miR-503-5p-dependent manner by targeting STAT3. AG-490 is expected to become a new candidate drug for the treatment of prostate cancer.

Wogonoside Inhibits Prostate Cancer Cell Growth and Metastasis via Regulating Wnt/β-Catenin Pathway and Epithelial-Mesenchymal Transition

Pharmacology ◽  
2019 ◽  
Vol 104 (5-6) ◽  
pp. 312-319 ◽  
Author(s):  
Can Wei ◽  
Junfeng Jing ◽  
Yanbin Zhang ◽  
Ling Fang
Keyword(s):  
Prostate Cancer ◽  
Cell Viability ◽  
Epithelial Mesenchymal Transition ◽  
Phase Cell ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Pc3 Cells ◽  
Gsk 3Β

Background: Wogonoside, an effective component of Scutellaria baicalensis extract, has recently become a hot topic for its newly discovered anticancer efficacy, but the underlying pharmacological mechanism is still unclear. In this study, we tested the inhibitory effects of wogonoside in human prostate cancer PC3 cells in vitro and vivo. Methods: The effects of wogonoside on cell viability, cycle progression, invasion, migration, and apoptosis were assessed in vitro. The levels of proteins in related signaling pathways were detected by western blotting assay. Finally, nude mouse tumorigenicity assay was conducted to detect the anticancer effect of wogonoside in vivo. Results: Wogonoside inhibited cell viability, invasive and migratory ability in a time- and dose-dependent manner. Flow cytometry indicated that wogonoside could induce cell apoptosis and S phase cell-cycle arrest. Mechanically, wogonoside suppressed the Wnt/β-catenin signaling pathway, and the level of p-glycogen synthase kinase-3β (GSK-3β; Ser9) was inhibited by wogonoside. The epithelial-mesenchymal transition (EMT) process was also reversed in PC3 cell line after wogonoside treatment. In vivo experiments showed that wogonoside inhibited tumor growth in xenograft mouse models. Conclusion: These findings revealed that wogonoside could suppress Wnt/β-catenin pathway and reversing the EMT process in PC3 cells. GSK-3β acts as a tumor suppressor in prostate cancer. Wogonoside may serve as an effective agent for treating prostate cancer.

scholarly journals Extracellular CIRP Induces an Inflammatory Phenotype in Pulmonary Fibroblasts via TLR4

2021 ◽  
Vol 12 ◽  
Author(s):  
Siavash Bolourani ◽  
Ezgi Sari ◽  
Max Brenner ◽  
Ping Wang
Keyword(s):  
Pulmonary Fibrosis ◽  
Inflammatory Cytokines ◽  
Rna Binding ◽  
Critical Role ◽  
Dependent Manner ◽  
Gene Expressions ◽  
Pulmonary Fibroblasts ◽  
Molecular Pattern ◽  
Fibrotic Process ◽  
Inflammatory Phenotype

Extracellular cold-inducible RNA-binding protein (eCIRP), a new damage-associated molecular pattern (DAMP), has been recently shown to play a critical role in promoting the development of bleomycin-induced pulmonary fibrosis. Although fibroblast activation is a critical component of the fibrotic process, the direct effects of eCIRP on fibroblasts have never been examined. We studied eCIRP’s role in the induction of inflammatory phenotype in pulmonary fibroblasts and its connection to bleomycin-induced pulmonary fibrosis in mice. We found that eCIRP causes the induction of proinflammatory cytokines and differentially expression-related pathways in a TLR4-dependent manner in pulmonary fibroblasts. Our analysis further showed that the accessory pathways MD2 and Myd88 are involved in the induction of inflammatory phenotype. In order to study the connection of the enrichment of these pathways in priming the microenvironment for pulmonary fibrosis, we investigated the gene expression profile of lung tissues from mice subjected to bleomycin-induced pulmonary fibrosis collected at various time points. We found that at day 14, which corresponds to the inflammatory-to-fibrotic transition phase after bleomycin injection, TLR4, MD2, and Myd88 were induced, and the transcriptome was differentially enriched for genes in those pathways. Furthermore, we also found that inflammatory cytokines gene expressions were induced, and the cellular responses to these inflammatory cytokines were differentially enriched on day 14. Overall, our results show that eCIRP induces inflammatory phenotype in pulmonary fibroblasts in a TLR4 dependent manner. This study sheds light on the mechanism by which eCIRP induced inflammatory fibroblasts, contributing to pulmonary fibrosis.

Tissue factor procoagulant activity of plasma microparticles is increased in patients with early-stage prostate cancer

2009 ◽  
Vol 101 (06) ◽  
pp. 1147-1155 ◽  
Author(s):  
Brigitte Spath ◽  
Martin Friedrich ◽  
Felix Kyoung-Hwan Chun ◽  
Guy Marx ◽  
Ali Amirkhosravi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Early Stage ◽  
Critical Role ◽  
Procoagulant Activity ◽  
Dependent Manner ◽  
Phase Reaction ◽  
Coagulation Activation ◽  
D Dimer

SummaryTissue factor (TF) plays a critical role in tumour growth and metastasis, and its enhanced release into plasma in association with cellular microparticles (MPs) has recently been associated with pathological cancer progression. We have previously demonstrated significantly elevated levels of plasma TF antigen as well as systemic coagulation and platelet activation in patients with localised prostate cancer. In this prospective study, we used a highly sensitive one-stage clotting assay to measure preoperative TF-specific procoagulant activity (PCA) of plasma MPs in 68 consecutive patients with early-stage prostate cancer to further explore the relevance of circulating TF in this tumour entity. Automated calibrated thrombography was used to monitor thrombin generation in cell-free plasma samples in the absence of exogenous TF or phospholipids. Compared to healthy male controls (n=20), patients had significantly increased levels of both D-dimer and TF-specific PCA of plasma MPs (p<0.001). Furthermore, MP-associated TF PCA was higher in patients with (n=29) than in those without (n=39) laboratory evidence of an acute-phase reaction (p=0.004) and decreased to normal levels within one week after radical prostatectomy. Overall, we found a significant correlation between TF-specific PCA of plasma MPs and plasma D-dimer (p=0.002), suggesting that plasma MPs contributed to in-vivo coagulation activation in a TF-dependent manner. Thrombin generation in plasma was also significantly increased in patients compared to controls (p<0.01). Collectively, our findings suggest that TF-specific PCA of plasma MPs contributes to intravascular coagulation activation in patients with early-stage prostate cancer and may represent a potential link between hypercoagulability, inflammation, and disease progression.

scholarly journals Synergistic Effect of Muramyldipeptide with Lipopolysaccharide or Lipoteichoic Acid To Induce Inflammatory Cytokines in Human Monocytic Cells in Culture

2001 ◽  
Vol 69 (4) ◽  
pp. 2045-2053 ◽  
Author(s):  
Shuhua Yang ◽  
Riyoko Tamai ◽  
Sachiko Akashi ◽  
Osamu Takeuchi ◽  
Shizuo Akira ◽  
...  
Keyword(s):  
Cell Surface ◽  
Synergistic Effect ◽  
Inflammatory Cytokines ◽  
Synergistic Effects ◽  
Lipoteichoic Acid ◽  
Dependent Manner ◽  
U937 Cells ◽  
Monocytic Cells ◽  
Enhanced Production ◽  
Tlr4 Mrna

ABSTRACT An analog of 1α,25-dihydroxyvitamin D3, 22-oxyacalcitriol (OCT), differentiated human monocytic THP-1 and U937 cells to express membrane CD14 and rendered the cells responsive to bacterial cell surface components. Both THP-1 and U937 cells expressed Toll-like receptor 4 (TLR4) on the cell surface and TLR4 mRNA in the cells, irrespective of OCT treatment. In contrast, OCT-treated U937 cells scarcely expressed TLR2 mRNA, while OCT-treated THP-1 cells expressed this transcript. Muramyldipeptide (MDP) by itself exhibited only a weak ability to induce secretion of inflammatory cytokines such as interleukin-8 (IL-8) in the OCT-differentiated THP-1 cells but showed marked synergistic effects with Salmonellalipopolysaccharide (LPS) or lipoteichoic acid (LTA) fromStaphylococcus aureus, both of which exhibited strong activities. Combinatory stimulation with LPS plus LTA did not show a synergistic effect on OCT-differentiated THP-1 cells. Similar results were observed in OCT-differentiated U937 cells, although combination experiments were carried out only with MDP plus LPS. Anti-CD14 monoclonal antibody (MAb) MY4, anti-TLR4 MAb HTA125, and the synthetic lipid A precursor LA-14-PP almost completely inhibited the IL-8-inducing activities of LTA as well as LPS on OCT-treated THP-1 cells, but these treatments increased MDP activity. OCT-treated THP-1 cells primed with MDP exhibited enhanced production of IL-8 upon stimulation with LPS, while the cells primed with LPS showed no change in production upon stimulation with MDP. MDP up-regulated mRNA expression of an adapter molecule to TLRs, MyD88, to an extent similar to that for LPS in OCT-treated THP-1 cells. These findings suggested that LTA as well as LPS activated human monocytic cells in a CD14- and TLR4-dependent manner, whereas MDP exhibited activity in a CD14-, TLR4-, and probably TLR2-independent manner and exhibited synergistic and priming effects on the cells for cytokine production in response to various bacterial components.

scholarly journals Downregulation of HMGA2 by Small Interfering RNA Affects the Survival, Migration, and Apoptosis of Prostate Cancer Cell Line

2021 ◽  
Author(s):  
Shima Khajouee ◽  
Elham Baghbani ◽  
Ali Mohammadi ◽  
Behzad Mansoori ◽  
Dariush Shanehbandi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Prostate Cancer Cell ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Dependent Manner ◽  
Pc3 Cells ◽  
The Impact

Purpose: To investigate the downregulation of High Mobility Group AT-hook 2 (HMGA2) expression by small interfering RNAs (siRNAs) in PC3 prostate cancer cell line. HMGA2 belongs to the non-histone chromatin-binding protein family that serves as a crucial regulator of gene transcription. The overexpression of this gene is positively correlated with various prostate cancer-related properties. Thus, HMGA2 is an emerging target in prostate cancer treatment. This study aimed to examine the impact of siRNAs targeting HMGA2 on the viability, migration, and apoptosis processes of the PC3 prostate cancer cell line. Methods: siRNA transfection was conducted with a liposome-mediated approach. The mRNA and protein expression levels for HMGA2 are evaluated by qRT-PCR and western blot analysis. The cytotoxic properties of HMGA2-siRNA were measured by MTT assay on PC3 cells. The migration of PC3 cells was measured by implementing a wound-healing assay. Apoptosis measurement was also quantified by TUNEL assay. Results: Transfection with siRNA significantly decreased both mRNA and protein levels of the HMGA2 gene in a dose-dependent manner after 48 hours. Also, we demonstrated that the knockdown of HMGA2 led to a reduction in cell viability, migration ability, and enhanced apoptosis of PC3 cells in vitro. Conclusion: Our findings recommend that the specific siRNA of HMGA2 may efficiently be able to decrease prostate cancer progression. Therefore, it may be a promising adjuvant treatment in prostate cancer.

scholarly journals Zoledronic Acid Elicits Proinflammatory Cytokine Profile in Osteolytic Prostate Cancer Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Yi-Chia Lin ◽  
Po-Cheng Liao ◽  
Te-Fu Tsai ◽  
Kuang-Yu Chou ◽  
Hung-En Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Cancer Cells ◽  
Metastatic Prostate Cancer ◽  
Prostate Cancer Cell ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Low Concentrations ◽  
Pc3 Cells ◽  
Inflammatory Profile

Zoledronic acid (ZA), a bisphosphonate used to prevent skeletal fractures in patients with cancers, was demonstrated to induce apoptosis in a number of cancer cells. Our previous study showed that ZA also induces autophagic cell death in metastatic prostate cancer cells. However, the clinical trials using ZA in the treatment of metastatic prostate cancer did not have a longer diseases-free period. Since most of ZA was attracted to the bone after administration, we hypothesized that local prostate cancer cells may evolve prosurvival pathways upon low concentration of ZA treatment. In this study, we investigated the inflammatory effects of ZA on osteolytic PC3 prostate cancer cell, since inflammation was reported to be related to cancer development and survival. Exposure of PC3 cells to various concentrations of ZA resulted in induction of apoptosis and autophagy. The expression of inflammatory biomarkers including interleukin 6 (IL-6), cyclooxygenase-2 (COX-2), and NF-κB was remarkably upregulated in response to ZA treatment in a dose- and time-dependent manner. The production of IL-6 was elevated upon ZA treatment. The antiapoptotic protein Bcl2 was increased with parallel increased level of IL-6. Our data suggest that treatment with low concentrations of ZA enhances the inflammatory profile and may serve as a prosurvival signaling pathway in PC3 cells.

scholarly journals Prostate-Derived ETS Factor (PDEF) Regulates Yes Associated Protein 1 (YAP1) in Prostate Cancer Cells: A Potential Cross-Talk between PDEF and Hippo Signaling

2019 ◽  
Author(s):  
Praveen Kumar Jaiswal ◽  
Suman Mohajan ◽  
Sweaty Koul ◽  
Fengtian Wang ◽  
Runhua Shi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Cross Talk ◽  
Hippo Pathway ◽  
Critical Role ◽  
Prostate Cancer Progression ◽  
Normal Prostate ◽  
Protein Levels ◽  
Pc3 Cells ◽  
The Hippo Pathway

PDEF is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation of its downstream effectors. In previous studies, we observed decreased levels of PDEF during prostate cancer progression. In the present studies, we evaluated the effects of PDEF on total and phospho (Ser-127)YAP1 protein(a downstream effector of the Hippo pathway) levels in PC3 cells, a line of castrate resistant prostate cancer. We observed that the expression of PDEF in PC3 cells resulted in increased increased phospho(Ser127) -YAP1 protein levels. Our immunofluorescence analysis for YAP1 revealed an increased cytoplasmic/nuclear ratio of YAP1 in PDEF-PC3 cells as compared to VC-PC3 cells, suggesting PDEF may play a critical role in modulating YAP1 phosphorylation, and by extension in the regulation of the Hippo pathway. We also observed a decrease in YAP1 protein levels in prostate cancer tissues as compared to normal prostate tissues. Our analysis of multiple publicly available clinical cohorts revealed a gradual decrease in YAP1 mRNA expression during prostate cancer progression and metastasis. This decrease was similar to the decrease in PDEF levels which we reported earlier. In addition we observed further decreased in PDEF and YAP1 expression in Neuro-Endocrine Prostate Cancer (NEPC), and a direct correlation between PDEF and YAP1 expression. To the best of our knowledge, these results provide the first demonstration of modulation of YAP1 by PDEF in any system and suggest a cross-talk between PDEF and the Hippo pathway.

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