scholarly journals Serum Levels of the Cytokine TWEAK Are Associated with Metabolic Status in Patients with Prostate Cancer and Modulate Cancer Cell Lipid Metabolism In Vitro

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4688
Author(s):  
Antonio Altuna-Coy ◽  
Xavier Ruiz-Plazas ◽  
Marta Alves-Santiago ◽  
José Segarra-Tomás ◽  
Matilde R. Chacón
Keyword(s):  
Prostate Cancer ◽  
Lipid Metabolism ◽  
Glucose Transporter ◽  
Specific Antigen ◽  
Serum Levels ◽  
Metabolic Effects ◽  
Lipid Uptake ◽  
Regulate Lipid Metabolism ◽  
Pparg Expression

Soluble TWEAK (sTWEAK) has been proposed as a prognostic biomarker of prostate cancer (PCa). We found that reduced serum levels of sTWEAK, together with higher levels of prostate-specific antigen and a higher HOMA-IR index, are independent predictors of PCa. We also showed that sTWEAK stimulus failed to alter the expression of glucose transporter genes (SLC2A4 and SLC2A1), but significantly reduced the expression of glucose metabolism-related genes (PFK, HK1 and PDK4) in PCa cells. The sTWEAK stimulation of PC-3 cells significantly increased the expression of the genes related to lipogenesis (ACACA and FASN), lipolysis (CPT1A and PNPLA2), lipid transport (FABP4 and CD36) and lipid regulation (SREBP-1 and PPARG) and increased the lipid uptake. Silencing the TWEAK receptor (Fn14) in PC-3 cells confirmed the observed lipid metabolic effects, as shown by the downregulation of ACACA, FASN, CPT1A, PNPLA2, FABP4, CD36, SREBP-1 and PPARG expression, which was paralleled by a reduction of FASN, CPT1A and FABP4 protein expression. Specific-signaling inhibitor assays show that ERK1/2 and AKT (ser473) phosphorylation can regulate lipid metabolism-related genes in PCa cells, pointing to the AKT locus as a possible target for PCa. Overall, our data support sTWEAK/Fn14 axis as a potential therapeutic target for PCa.

Platelet activation, coagulation and angiogenesis in breast and prostate carcinoma

2004 ◽  
Vol 92 (07) ◽  
pp. 185-190 ◽  
Author(s):  
Graham Caine ◽  
Gregory Lip ◽  
Paul Stonelake ◽  
Peter Ryan ◽  
Andrew Blann
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Platelet Activation ◽  
Plasma Levels ◽  
Specific Antigen ◽  
Serum Levels ◽  
Soluble P ◽  
Endothelial Growth Factor ◽  
D Dimer

SummaryIn health, haemostasis and angiogenesis are tightly regulated processes, but may become deregulated in cancer. Recent evidence suggests that platelet activation may link these processes as platelets can release angiogenic factors such as vascular endothelial growth factor (VEGF). Furthermore, inflammation has also been implicated in regulating both coagulation and angiogenesis, possibly by activating platelets directly and increasing, for example, plasma fibrinogen. We hypothesized relationships between plasma markers of the processes in two common forms of cancer. Plasma levels of VEGF (reflecting angiogenesis), soluble P-selectin, (marking platelet activation), tissue factor [TF], fibrinogen and fibrin D-dimer (coagulation markers), and serum levels of IL-6 (inflammation) were measured by ELISA in 30 patients with biopsy-proven breast cancer, 30 patients with biopsy-proven prostate cancer, and 30 ageand sex-matched controls for each group. Prostate specific antigen was also measured in the men. Release of VEGF from IL-6 stimulated platelets was assessed by ELISA. Plasma levels of IL-6 (P <0.02), VEGF, soluble P-selectin, fibrinogen, and fibrin D-dimer (all p <0.01) were significantly raised in breast cancer, whereas VEGF, soluble P-selectin, fibrin D-dimer (all p <0.01) and fibrinogen (p <0.05) were significantly raised in prostate cancer. Significant correlations were found between IL-6 and VEGF (p <0.01), and IL-6 and soluble P-selectin (p = 0.038) in breast cancer. Further experiments demonstrated an in vitro IL-6 induced dose-dependent release of VEGF from platelets. In conclusion, strong relationships between IL6 and VEGF, but not with coagulation or platelet markers, and release of VEGF from IL-6 stimulated platelets, suggest a role for inflammation and platelets in angiogenesis.

scholarly journals Prognostic role of docetaxel-induced suppression of free testosterone serum levels in metastatic prostate cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paula Kappler ◽  
Michael A. Morgan ◽  
Philipp Ivanyi ◽  
Stefan J. Brunotte ◽  
Arnold Ganser ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Cox Regression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Biologically Active ◽  
Free Form ◽  
Total Testosterone ◽  
The Impact

AbstractTo date, only few data concerning the biologically active, free form of testosterone (FT) are available in metastatic prostate cancer (mPC) and the impact of FT on disease, therapy and outcome is largely unknown. We retrospectively studied the effect of docetaxel on FT and total testosterone (TT) serum levels in 67 mPC patients monitored between April 2008 and November 2020. FT and TT levels were measured before and weekly during therapy. The primary endpoint was overall survival (OS). Secondary endpoints were prostate-specific antigen response and radiographic response (PSAR, RR), progression-free survival (PFS), FT/TT levels and safety. Median FT and TT serum levels were completely suppressed to below the detection limit during docetaxel treatment (FT: from 0.32 to < 0.18 pg/mL and TT: from 0.12 to < 0.05 ng/mL, respectively). Multivariate Cox regression analyses identified requirement of non-narcotics, PSAR, complete FT suppression and FT nadir values < 0.18 pg/mL as independent parameters for PFS. Prior androgen-receptor targeted therapy (ART), soft tissue metastasis and complete FT suppression were independent prognostic factors for OS. FT was not predictive for treatment outcome in mPC patients with a history of ART.

scholarly journals YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Hsiu-Chi Lee ◽  
Chien-Hui Ou ◽  
Yun-Chen Huang ◽  
Pei-Chi Hou ◽  
Chad J. Creighton ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lipid Metabolism ◽  
Critical Issue ◽  
Castration Resistant Prostate Cancer ◽  
Cancer Stemness ◽  
New Treatment ◽  
Underlying Mechanisms ◽  
Transcriptional Complex

AbstractMetastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.

Abstract 121: Pro-inflammatory Cytokine Ifng Modulates Hepatic Sortilin Expression and Lipid Metabolism.

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
John Pirault ◽  
Konstantinos Polyzos ◽  
Daniel F Ketelhuth ◽  
Göran K Hansson
Keyword(s):  
Lipid Metabolism ◽  
Binding Sites ◽  
In Silico ◽  
In Silico Analysis ◽  
Lipid Uptake ◽  
Regulatory T Lymphocytes ◽  
Inflammatory Conditions ◽  
Ldl Particles ◽  
Inflammatory Milieu

Rationale: Hypercholesterolemia and immunity are two major risk factors for cardiovascular diseases (CVDs). Yet, we reported increased atherosclerosis upon depletion of regulatory T lymphocytes (Tregs). The effect was associated with increased hepatic inflammation and reduction of Sortilin expression and lipid uptake in the liver. Objective: To define how inflammatory milieu in the liver can modulate Sortilin and lipid metabolism. Methods: To reproduce the inflammatory milieu, hepatocytes (AML-12) were treated in vitro with IFNg. Expression of genes and proteins of interest were followed by qPCR and western blot. In silico method was used to find binding sites of signal transducer and activator of transcription (STAT1) on Sortilin, confirmed later by chromatin immune precipitation assays (Chip). Lipid uptake by hepatocytes was assessed via incubation of cells with radioactive lipoproteins. Results: Culture of AML-12 cells with IFNg induced the phosphorylation of STAT1 showing an active signaling pathway. In the same inflammatory conditions, Sort1 mRNA is decreased meanwhile its inhibitor (Atf3) expression is increased. Kinetic experiments revealed the reduction of Sortilin after 12 hours of culture, suggesting a post-transcriptional regulation of Sort1 by STAT1. In silico analysis revealed putative binding sites for STAT1 on Sortilin gene which was confirmed by chromatin immunoprecipitation assay (Chip). IFNg treated hepatocytes that were incubated with radioactive lipoproteins demonstrated a reduced uptake capacity of VLDL and LDL particles compared to control cultures. Conclusion: All together, these results suggest that inflammation through production of IFNg is able to directly modulate the lipid metabolism in hepatocytes by acting on Sortilin expression.

The Activity of Urolithin A and M4 Valerolactone, Colonic Microbiota Metabolites of Polyphenols, in a Prostate Cancer In Vitro Model

Planta Medica ◽  
2018 ◽  
Vol 85 (02) ◽  
pp. 118-125 ◽  
Author(s):  
Iwona Stanisławska ◽  
Sebastian Granica ◽  
Jakub Piwowarski ◽  
Joanna Szawkało ◽  
Krzysztof Wiązecki ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
In Vitro Model ◽  
Specific Antigen ◽  
Lncap Cells ◽  
Isobolographic Analysis ◽  
Human System ◽  
Urolithin A ◽  
Vitro Model ◽  
Induced Apoptosis

AbstractThe gut microbiota-derived metabolites of ellagitannins and green tea catechins, urolithin A (uroA) and 5-(3′,4′,5′-trihydroxyphenyl)-γ-valerolactone (M4), respectively, are among the main compounds absorbed into human system after ingestion of these polyphenols. The aim of this study was to establish the effects of M4, uroA, and their combinations on LNCaP cells, an androgen dependent prostate cancer in vitro model.. The LNCaP cells were incubated with increasing concentrations of tested metabolites. The cell proliferation was determined by measurement of DNA-bisbenzimide H 33 258 complexes fluorescence. The isobolographic analysis was used to establish the type of interaction between metabolites. The apoptosis, androgen receptor (AR) localization, and phosphorylation of Akt kinase were measured by flow cytometry. Prostate-specific antigen (PSA) secretion was determined by ELISA. M4 showed modest antiproliferative activity in LNCaP cells (IC50 = 117 µM; CI: 81 – 154). UroA decreased proliferation (IC50 = 32.7 µM; CI: 24.3 – 41.1) and induced apoptosis of LNCaP cells. The mixture of M4 with uroA had synergistic antiproliferative effect. Moreover, M4 potentiated inhibition of PSA secretion and enhanced retention of AR in cytoplasm caused by uroA. Interestingly, uroA increased levels of pSer473 Akt in LNCaP cells. These results show that colonic metabolites may contribute to chemoprevention of prostate cancer by varied polyphenol-rich diet or composite polyphenol preparations.

scholarly journals FABP5 coordinates lipid signaling that promotes prostate cancer metastasis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gregory Carbonetti ◽  
Tessa Wilpshaar ◽  
Jessie Kroonen ◽  
Keith Studholme ◽  
Cynthia Converso ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Fatty Acid Synthase ◽  
Cancer Metastasis ◽  
Receptor Activation ◽  
Lipid Signaling ◽  
Fatty Acid Binding

AbstractProstate cancer (PCa) is defined by dysregulated lipid signaling and is characterized by upregulation of lipid metabolism-related genes including fatty acid binding protein 5 (FABP5), fatty acid synthase (FASN), and monoacylglycerol lipase (MAGL). FASN and MAGL are enzymes that generate cellular fatty acid pools while FABP5 is an intracellular chaperone that delivers fatty acids to nuclear receptors to enhance PCa metastasis. Since FABP5, FASN, and MAGL have been independently implicated in PCa progression, we hypothesized that FABP5 represents a central mechanism linking cytosolic lipid metabolism to pro-metastatic nuclear receptor signaling. Here, we show that the abilities of FASN and MAGL to promote nuclear receptor activation and PCa metastasis are critically dependent upon co-expression of FABP5 in vitro and in vivo. Our findings position FABP5 as a key driver of lipid-mediated metastasis and suggest that disruption of lipid signaling via FABP5 inhibition may constitute a new avenue to treat metastatic PCa.

scholarly journals Prospective study on the effect of short-term androgen deprivation therapy on PSMA uptake evaluated with 68Ga-PSMA-11 PET/MRI in men with treatment-naïve prostate cancer

2019 ◽  
Vol 47 (3) ◽  
pp. 665-673 ◽  
Author(s):  
Otto Ettala ◽  
Simona Malaspina ◽  
Terhi Tuokkola ◽  
Pauliina Luoto ◽  
Eliisa Löyttyniemi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Androgen Deprivation Therapy ◽  
Time Course ◽  
Specific Antigen ◽  
Androgen Deprivation ◽  
Short Term ◽  
Psma Pet ◽  
Treatment Naïve

Abstract Purpose Based on in vitro studies, it is known that androgen deprivation therapy (ADT) increases prostate-specific membrane antigen (PSMA) expression. Therefore, we hypothesised that ADT improves the performance of PSMA-PET imaging in primary staging of prostate cancer. The purpose of the study was to demonstrate the time course effect of ADT on PSMA uptake in different types of metastatic lesions evaluated with 68Ga-PSMA-11 PET/MRI. Methods Nine men with treatment-naïve prostate cancer were enrolled to a prospective, registered (NCT03313726) clinical trial. A 68Ga-PSMA-11 PET/MRI was performed once before and 3 times post-ADT (degarelix, Firmagon). Change of maximum standardised uptake values (SUVmax) in prostate, lymph nodes, bone metastases, and physiologically PSMA-avid organs were evaluated in a time frame of 1–8 weeks. Results All patients reached castration levels within 10 days, and 50% decrease in prostate-specific antigen (PSA) concentration was observed 14 days post-ADT. A heterogeneous increase in PSMA uptake was observed 3 to 4 weeks post-ADT. This phenomenon was definitively more evident in bone metastases: 13 (57%) of the metastasis, with a mean (range) SUVmax increase of 77% (8–238%). In one patient, already having bone metastases at baseline, three new bone metastases were observed post-ADT. Of lesions with reduced SUVmax, none disappeared. Conclusions Both in patient and region level, increase in PSMA uptake post-ADT is heterogenous and is seen most evidently in bone metastases. Preliminary results on a small cohort of patients suggest the clinical impact of ADT on improving the performance of 68Ga-PSMA PET in staging seems to be minor. However, the optimal imaging time point might be 3 to 4 weeks post-ADT. Since none of the metastases with decreasing SUVmax disappeared, it seems that short-term usage of ADT does not interfere with the interpretation of 68Ga-PSMA PET. Trial registration NCT03313726, registered 18 October 2017; EUDRA-CT, 2017-002345-29.

scholarly journals Reinduction of Hormone Sensitivity to Goserelin following Chemotherapy with Vinorelbine in Castration-Resistant Prostate Cancer

2010 ◽  
Vol 10 ◽  
pp. 1814-1817
Author(s):  
Tal Grenader ◽  
Anthony Goldberg
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Serum Levels ◽  
Symptomatic Improvement ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Luteinizing Hormone Releasing Hormone ◽  
Androgen Ablation ◽  
Castration Resistant ◽  
Cessation Of Treatment

Primary androgen ablation leads to symptomatic improvement and a reduction in prostate-specific antigen (PSA) serum levels in patients with advanced prostate cancer, but all patients eventually become refractory to hormone therapy with progression of the disease and a life expectancy of about a year. We describe a patient who developed castration resistance, was treated with vinorelbine, and continues to be progression free on therapy with luteinizing hormone releasing hormone agonists alone, more than 2.5 years following cessation of treatment with vinorelbine.

The Association of PSA-IGM and Total PSA Improves the Diagnosis of Prostate Cancer

2009 ◽  
Vol 24 (3) ◽  
pp. 212-212
Author(s):  
Danilo Zani ◽  
Silvia Costa ◽  
Lorenzo Gatti ◽  
Nicola Pesenti ◽  
Alberto Pettenò ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Diagnostic Accuracy ◽  
Prostate Biopsy ◽  
Specific Antigen ◽  
Digital Rectal Examination ◽  
Serum Levels ◽  
Immunoglobulin M ◽  
Diagnostic Tools ◽  
Psa Test ◽  
Total Psa

Background and aim The specific causes of prostate cancer (Pca) are unknown but the main risk factors of tumor development are associated with age, genetic factors, ethnicity, diet and lifestyle. Prostate cancer is rare in men under 45 years of age, but becomes more common with advancing age. The main diagnostic tools for demonstrating the presence of PCa include digital rectal examination, transrectal ultrasonography, and serum measurement of prostate specific antigen (PSA) followed by prostate biopsy for confirmation of the diagnosis. While the measurement of PSA levels has revolutionized the diagnosis of PCa, it has also increased its overdiagnosis due to the poor diagnostic accuracy. Scientific evidence indicates that biomarkers for different types of cancer such as liver and colorectal cancer circulate in the blood associated with immunoglobulin M (IgM) to form complexes that allow a better diagnosis in comparison to circulating free biomarkers. In prostate cancer it has been demonstrated that testing for serum levels of the PSA-IgM immune complex improves the diagnostic performance of total PSA. The aim of this study was to evaluate the diagnostic accuracy of PSA-IgM compared to total PSA for the selection of patients to be submitted to transrectal ultrasound-guided prostate biopsy. Patients and methods Serum samples from 67 male patients, 33 affected by PCa with a Gleason score from 5 to 7, and 34 affected by benign prostate hypertrophy (BPH), were collected by the Department of Urology of the Spedali Civili of Brescia. The samples were immediately snap frozen at −80°C. Serum levels of PSA-IgM were assessed using Prostate-IC (Xeptagen, Italy) while PSA levels were determined with the Immulite 2000 of Medical Systems S.p.A. Results Patients were stratified into 2 groups according to age; the first group consisted of 24 patients with PCa and 20 with BPH aged between 60 and 70 years and the second group consisted of 9 patients with PCa and 14 with BPH aged between 70 and 80 years. Serum levels of PSA and PSA-IgM were analyzed in the 2 groups using cutoff values of 4 ng/mL for PSA and 145 AU/mL for PSA-IgM. In the first group, 1 8 of 24 PCa patients were positive for PSA (75% sensitivity) with a specificity of 50% (10 of 20 BPH patients), and 1 0 of 24 PCa patients were positive with the PSA-IgM assay (42% sensitivity), which had a higher specificity (70%; 6 of 20 BPH patients). The combination of both biomarkers resulted in a sensitivity of 38% (9 of 24 patients with PCa) but showed a significant improvement in specificity up to 90%, since 18 of 20 patients with BPH were negative for at least one test. In the second group of patients aged 70 to 80 years, the PSA test had a sensitivity of 67% (6/9 PCa patients) and a specificity of 78% (3/14 BPH patients) compared with a sensitivity of 44% for the PSA-IgM test (4/9 PCa patients) with a specificity of 71% (4/14 BPH patients). The combination of PSA and PSA-IgM had a sensitivity of 30% (3/9) but the highest specificity (93%, 13/14 BPH patients). Conclusion The results of the study demonstrate the diagnostic value of the PSA-IgM assay compared with the total PSA test. The combination of PSA-IgM with total PSA was the best approach to reduce the number of false-positive results, thus improving the diagnosis of prostate cancer.

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