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Resistance to anti-androgens and chemotherapy (Cx) limits therapeutic options for patients with hormone-sensitive (mHSPC) and hormone-resistant prostate cancer (mCRPC). In this context, upregulation of the glucocorticoid receptor (GR) has been identified as a potential bypass mechanism in mCRPC, and a combination of docetaxel and mifepristone (Doc + RU-486), an inhibitor of GR, re-sensitized docetaxel-resistant cell models to Cx. This study was designed to elucidate the molecular mechanisms responsible for this phenomenon. RNA sequencing (RNA-seq) in docetaxel-resistant PCa cell models after Doc + RU-486 treatment with consecutive functional assays were performed. Expression of selected proteins was verified in prostatic tissue from prostate cancer (PCa) patients with progressive disease. Treatment with Doc + RU-486 significantly reduced cancer cell viability and RNA-Seq. revealed sterol regulatory element of binding transcription factor 1 (SREBF-1), a transcription factor of cholesterol and lipid biosynthesis, as a significantly downregulated target. Functional assays confirmed that SREBF-1 downregulation is partially responsible for this observation. In concordance, SREBF-1 knockdown and pharmacological SREBP inhibition, together with other key enzymes in the cholesterol pathway, showed similar results. Furthermore, SREBF-1 expression is significantly elevated in advanced PCa tissues, demonstrating its potential involvement in tumor progression and emerging therapy resistance. Therefore, specific inhibition of cholesterol and lipid biosynthesis might also target Cx-resistant cancer cells and represent a potential additive future therapeutic option to improve mCRPC therapy.
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Continued exploration of the androgen receptor (AR) is crucial, as it plays pivotal roles in diverse diseases such as prostate cancer (PCa), serving as a significant therapeutic focus. Therefore, the Department of Urology Dresden hosted an international meeting for scientists and clinical oncologists to discuss the newest advances in AR research. The 2nd International Androgen Receptor Symposium was held in Dresden, Saxony, Germany, from 26-27.04.2024, organised by Dr. Holger H.H. Erb. Following the format of the first meeting, more than 35 scientists from 8 countries attended the event to discuss recent developments, research challenges, and identification of venues in AR research. An important new feature was the involvement of PhD students and young investigators, acknowledging the high scientific quality of their work. The symposium included three covers: new advances from clinical research, basic and translational research, and novel strategies to target AR. Moreover, based on its increasing clinical relevance, a PSMA theranostic mini-symposium was added at the end of the AR symposium to allow the audience to discuss the newest advances in PSMA theranostic. This report focuses on the highlights and discussions of the meeting.
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Neoplasias da Próstata , Receptores Androgênicos , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genéticaRESUMO
Serum prostate-specific antigen (PSA), its derivatives, and magnetic resonance tomography (MRI) lack sufficient specificity and sensitivity for the prediction of risk reclassification of prostate cancer (PCa) patients on active surveillance (AS). We investigated selected transcripts in urinary extracellular vesicles (uEV) from PCa patients on AS to predict PCa risk reclassification (defined by ISUP 1 with PSA > 10 ng/mL or ISUP 2-5 with any PSA level) in control biopsy. Before the control biopsy, urine samples were prospectively collected from 72 patients, of whom 43% were reclassified during AS. Following RNA isolation from uEV, multiplexed reverse transcription, and pre-amplification, 29 PCa-associated transcripts were quantified by quantitative PCR. The predictive ability of the transcripts to indicate PCa risk reclassification was assessed by receiver operating characteristic (ROC) curve analyses via calculation of the area under the curve (AUC) and was then compared to clinical parameters followed by multivariate regression analysis. ROC curve analyses revealed a predictive potential for AMACR, HPN, MALAT1, PCA3, and PCAT29 (AUC = 0.614-0.655, p < 0.1). PSA, PSA density, PSA velocity, and MRI maxPI-RADS showed AUC values of 0.681-0.747 (p < 0.05), with accuracies for indicating a PCa risk reclassification of 64-68%. A model including AMACR, MALAT1, PCAT29, PSA density, and MRI maxPI-RADS resulted in an AUC of 0.867 (p < 0.001) with a sensitivity, specificity, and accuracy of 87%, 83%, and 85%, respectively, thus surpassing the predictive power of the individual markers. These findings highlight the potential of uEV transcripts in combination with clinical parameters as monitoring markers during the AS of PCa.
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BACKGROUND/AIM: The cytoprotective heat shock protein 27 (HSP27) acts as a protein chaperone, antioxidant, and apoptosis regulator and is involved in cytoskeletal remodeling in prostate cancer. This study was designed to assess the effect of prostate cancer therapeutics on HSP27 to identify drugs that may benefit from an HSP27 inhibitor combination therapy. MATERIALS AND METHODS: Cell counting was utilized to assess drug treatment efficiency. Changes in protein levels after drug treatment were assessed using western blot analysis. RESULTS: Abiraterone, cabazitaxel, docetaxel and enzalutamide significantly reduced cell proliferation in LNCaP and PC3 cells. Treatment with abiraterone and enzalutamide led to a significant reduction in HSP27 protein levels. In contrast, treatment with cabazitaxel and docetaxel did not change the HSP27 protein levels. CONCLUSION: Treatment with abiraterone and enzalutamide reduces HSP27 protein in an AR-independent manner and thus suppresses HSP27-correlated resistance mechanisms. However, docetaxel and cabazitaxel do not alter HSP27 protein levels, so that taxanes' efficacy may be enhanced by combining them with HSP27-inhibiting drugs.
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Androstenos , Antineoplásicos , Benzamidas , Proliferação de Células , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Proteínas de Choque Térmico HSP27 , Nitrilas , Feniltioidantoína , Neoplasias da Próstata , Taxoides , Humanos , Masculino , Taxoides/farmacologia , Taxoides/uso terapêutico , Docetaxel/farmacologia , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Proteínas de Choque Térmico HSP27/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Androstenos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chaperonas Moleculares/metabolismo , Proteínas de Choque Térmico/metabolismoRESUMO
Docetaxel (DX) serves as a palliative treatment option for metastatic prostate cancer (PCa). Despite initial remission, acquired DX resistance is inevitable. The mechanisms behind DX resistance have not yet been deciphered, but a mesenchymal phenotype is associated with DX resistance. Mesenchymal phenotypes have been linked to metabolic rewiring, obtaining most ATP production by oxidative phosphorylation (OXPHOS) powered substantially by glutamine (Gln). Likewise, Gln is known to play an essential role in modulating bioenergetic, redox homeostasis and autophagy. Herein, investigations of Gln deprivation on DX-sensitive and -resistant (DR) PCa cells revealed that the DR cell sub-lines were susceptible to Gln deprivation. Mechanistically, Gln deprivation reduced OXPHOS and ATP levels, causing a disturbance in cell cycle progression. Genetic and chemical inhibition of the Gln-metabolism key protein GLS1 could validate the Gln deprivation results, thereby representing a valid therapeutic target. Moreover, immunohistological investigation of GLS1 revealed a high-expressing GLS1 subgroup post-docetaxel failure, exhibiting low overall survival. This subgroup presents an intriguing opportunity for targeted therapy focusing on glutamine metabolism. Thus, these findings highlight a possible clinical rationale for the chemical inhibition of GLS1 as a therapeutic strategy to target mesenchymal DR PCa cells, thereby delaying accelerated tumour progression.
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Proliferação de Células , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Glutamina , Neoplasias da Próstata , Masculino , Humanos , Glutamina/metabolismo , Docetaxel/farmacologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Fosforilação Oxidativa/efeitos dos fármacos , Glutaminase/metabolismo , Glutaminase/antagonistas & inibidores , Glutaminase/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
PURPOSE: We assessed factors that affect the utilization of sperm cryopreservation before 2021, when patients covered expenses, and the influence on quality of life. METHODS: Between 2011 and 2021, testicular cancer survivors (TCS) at our clinic completed a questionnaire, including EORTC QLQ-TC26, covering sperm cryopreservation, sociodemographic details, post-treatment births, and artificial insemination. RESULTS: After 5.7 ± 3.0 years, 279 participants (64%) responded to the questionnaire. Among them, 33% (91/279) of testicular cancer survivors chose sperm cryopreservation prior to treatment, with 11% (10/91) using it for insemination. Conversely, 2% (3/188) without cryopreservation reported unfulfilled desire to have children. Univariate analysis showed TCS with cryopreservation were younger (30.6 ± 7.1 (35 (21-59)) vs. 42.4 ± 10.9 (48 (22-81)) years; p = 0.001), had a lower BMI (24.2 ± 3.3 vs. 26.6 ± 4.6 kg/m2; p = 0.009) and a lower Charlson Score (> 3: 36% vs. 60%; p < 0.001). Multivariate analysis revealed older age (≥ 37 years: OR 13.1 (5.5-31.2), p < 0.001) and lower education (middle school or less: OR 3.3 (1.6-6.9), p = 0.001) as independent factors associated with not undergoing cryopreservation. Regarding quality of life, multivariate analysis identified a lower infertility anxiety score (OR 4.3 (2.0-9.0), p < 0.001) and higher age (≥ 44 years: OR 5.4 (2.6-11.3); p < 0.001) as predictors for the absence of prior cryopreservation. CONCLUSIONS: Age and education seem to impact the choice of undergoing paid sperm cryopreservation. Urologists should inform testicular cancer patients about costs and coverage. Importantly, the occurrence of unmet desires for parenthood is minimal among those who forego cryopreservation.
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Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Criança , Humanos , Masculino , Adulto , Neoplasias Testiculares/terapia , Qualidade de Vida , Sêmen , Criopreservação , EspermatozoidesRESUMO
PURPOSE: Cabozantinib (CAB) as monotherapy or in combination with immune checkpoint inhibitors is used for systemic treatment of metastatic renal cell carcinoma (mRCC). However, little is known about predictors of treatment response to CAB. For this reason, known genomic drivers were examined to identify potential predictors of treatment response with CAB. METHODS: Twenty mRCC patients receiving monotherapy (≥ first-line) with CAB were prospectively included. DNA was extracted from archived primary tumors or metastatic tissue. Targeted DNA sequencing was performed using a gene panel including 328 genes (QIAseq Targeted DNA V3 Panel, Qiagen). The variant evaluation was performed using Varsome. The endpoints were treatment-failure-free-survival (TFFS) to CAB. RESULTS: 26% of patients received systemic RCC treatment as the primary option. Six patients were treated with CAB in first-line (1L) and 12 patients in ≥ 2L. The median follow-up after initiation of systemic treatment was 26.7 months (mo). The PBRM1 (7 alleles), SETD2 (7 alleles), VHL (11 alleles), and CHEK2 (14 alleles) genes were most frequently altered. The median time to TFFS was 10.5 mo (95% confidence interval (CI) 6.2-14.7 mo). There was a longer treatment response to CAB in patients with alterations of the SETD2 gene (SETD2 alteration median TFFS not reached vs. no SETD2 alterations 8.4 mo (95% CI 5.2-11.6 mo); p = 0.024). CONCLUSION: Pathogenic variant genes may indicate treatment response to systemic therapy in mRCC. Patients with alterations of the SETD2 gene show longer responses to CAB treatment.
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Anilidas , Carcinoma de Células Renais , Neoplasias Renais , Piridinas , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Genômica , DNARESUMO
Rationale: Current therapies for metastatic osseous disease frequently fail to provide a durable treatment response. To date, there are only limited therapeutic options for metastatic prostate cancer, the mechanisms that drive the survival of metastasis-initiating cells are poorly characterized, and reliable prognostic markers are missing. A high aldehyde dehydrogenase (ALDH) activity has been long considered a marker of cancer stem cells (CSC). Our study characterized a differential role of ALDH1A1 and ALDH1A3 genes as regulators of prostate cancer progression and metastatic growth. Methods: By genetic silencing of ALDH1A1 and ALDH1A3 in vitro, in xenografted zebrafish and murine models, and by comparative immunohistochemical analyses of benign, primary tumor, and metastatic specimens from patients with prostate cancer, we demonstrated that ALDH1A1 and ALDH1A3 maintain the CSC phenotype and radioresistance and regulate bone metastasis-initiating cells. We have validated ALDH1A1 and ALDH1A3 as potential biomarkers of clinical outcomes in the independent cohorts of patients with PCa. Furthermore, by RNAseq, chromatin immunoprecipitation (ChIP), and biostatistics analyses, we suggested the molecular mechanisms explaining the role of ALDH1A1 in PCa progression. Results: We found that aldehyde dehydrogenase protein ALDH1A1 positively regulates tumor cell survival in circulation, extravasation, and metastatic dissemination, whereas ALDH1A3 plays the opposite role. ALDH1A1 and ALDH1A3 are differentially expressed in metastatic tumors of patients with prostate cancer, and their expression levels oppositely correlate with clinical outcomes. Prostate cancer progression is associated with the increasing interplay of ALDH1A1 with androgen receptor (AR) and retinoid receptor (RAR) transcriptional programs. Polo-like kinase 3 (PLK3) was identified as a transcriptional target oppositely regulated by ALDH1A1 and ALDH1A3 genes in RAR and AR-dependent manner. PLK3 contributes to the control of prostate cancer cell proliferation, migration, DNA repair, and radioresistance. ALDH1A1 gain in prostate cancer bone metastases is associated with high PLK3 expression. Conclusion: This report provides the first evidence that ALDH1A1 and PLK3 could serve as biomarkers to predict metastatic dissemination and radiotherapy resistance in patients with prostate cancer and could be potential therapeutic targets to eliminate metastasis-initiating and radioresistant tumor cell populations.
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Neoplasias da Próstata , Receptores Androgênicos , Masculino , Humanos , Animais , Camundongos , Peixe-Zebra/metabolismo , Linhagem Celular Tumoral , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Neoplasias da Próstata/genética , Biomarcadores , Família Aldeído Desidrogenase 1 , Retinal DesidrogenaseRESUMO
The androgen receptor (AR) is a crucial player in various aspects of male reproduction and has been associated with the development and progression of prostate cancer (PCa). Therefore, the protein is the linchpin of current PCa therapies. Despite great research efforts, the AR signaling pathway has still not been deciphered, and the emergence of resistance is still the biggest problem in PCa treatment. To discuss the latest developments in AR research, the "1st International Androgen Receptor Symposium" offered a forum for the exchange of clinical and scientific innovations around the role of the AR in prostate cancer (PCa) and to stimulate new collaborative interactions among leading scientists from basic, translational, and clinical research. The symposium included three sessions covering preclinical studies, prognostic and diagnostic biomarkers, and ongoing prostate cancer clinical trials. In addition, a panel discussion about the future direction of androgen deprivation therapy and anti-AR therapy in PCa was conducted. Therefore, the newest insights and developments in therapeutic strategies and biomarkers are discussed in this report.
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Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Receptores Androgênicos/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Antagonistas de Androgênios/uso terapêutico , Transdução de Sinais , BiomarcadoresRESUMO
Despite significant therapeutic advances in recent years, treatment of metastatic prostate cancer (PCa) remains palliative, owing to the inevitable occurrence of drug resistance. There is increasing evidence that epithelial glucocorticoid receptor (GR) signaling and changes in the tumor-microenvironment (TME) play important roles in this process. Since glucocorticoids (GCs) are used as concomitant medications in the course of PCa treatment, it is essential to investigate the impact of GCs on stromal GR signaling in the TME. Therefore, general GR mRNA and protein expression was assessed in radical prostatectomy specimens and metastatic lesions. Elevated stromal GR signaling after GC treatment resulted in altered GR-target gene, soluble protein expression, and in a morphology change of immortalized and primary isolated cancer-associated fibroblasts (CAFs). Subsequently, these changes affected proliferation, colony formation, and 3D-spheroid growth of multiple epithelial PCa cell models. Altered expression of extra-cellular matrix (ECM) and adhesion-related proteins led to an ECM remodeling. Notably, androgen receptor pathway inhibitor treatments did not affect CAF viability. Our findings demonstrate that GC-mediated elevated GR signaling has a major impact on the CAF secretome and the ECM architecture. GC-treated fibroblasts significantly influence epithelial tumor cell growth and must be considered in future therapeutic strategies.
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Fibroblastos Associados a Câncer , Neoplasias da Próstata , Masculino , Humanos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Glucocorticoides/metabolismo , Próstata/patologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Microambiente Tumoral , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Fibroblastos/metabolismo , Fibroblastos Associados a Câncer/metabolismoRESUMO
BACKGROUND/AIM: PD-L1 inhibitors have been approved for cisplatin-ineligible urothelial cancer patients relapsing after radical cystectomy. A prerequisite for therapy is a positive PD-L1 expression in the tumor tissue, whereas no options are available for patients with negative PD-L1 status. However, studies revealed that many PD-L1-negative patients also responded to PD-L1 therapy. This study investigated the feasibility of PD-L1 mRNA complementary RNA in situ hybridization (RNAish) analysis to detect PD-L1-responders independent of PD-L1 protein status. MATERIALS AND METHODS: Immunohistochemistry and RNA in situ hybridization were used to assess PD-L1 protein and mRNA in radical cystectomy tissue from patients with advanced and metastasized urothelial cancer. RESULTS: In this study, PD-L1 protein and mRNA were detected in ≥90% of the examined tissue. Positive PD-L1 mRNA expression (≥1%) on TC and IC could be evaluated in 77% and 31% of the cases, respectively. Moreover, scatterplot analysis revealed a PD-L1 mRNA positive and PD-L1 protein negative subpopulation. According to the CPS score, positive PD-L1 protein expression could be evaluated in 88% and positive PD-L1 mRNA expression in 71% of the cases. Scatterplot analysis of the CPS scores revealed a CPS protein negative but CPS mRNA positive small subpopulation. CONCLUSION: The feasibility of RNAish on formalin-fixed tissue could be proven. Moreover, complementary PD-L1 RNAish identified a sub-population of PD-L1 protein-negative and PD-L1 mRNA-positive patients, which may benefit from PD-L1 therapy.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Antígeno B7-H1/metabolismo , RNA Mensageiro/genética , Recidiva Local de Neoplasia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/metabolismo , Carcinoma de Células de Transição/patologia , Biomarcadores Tumorais/metabolismoRESUMO
PURPOSE: Retroperitoneal lymph node dissection (RPLND) for germ cell tumours is a challenging procedure that may present relevant complications. The purpose was to analyse postoperative complications and identify risk factors for major complications. METHODS: This is a retrospective unicentric analysis of a large cohort of 295 RPLNDs from 1992 to 2020. Early complications (30 days) and late complications (31-180 days) were classified according to the ClavienâDindo classification. The influence of surgical, patient-specific, and tumour-specific parameters on grade III-V complications was analysed in univariate and multivariate logistic regression models. RESULTS: A total of 232 were postchemotherapy RPLNDs, and 63 were primary RPLNDs. Early postoperative complications were found to be grades I-II in 58.6% (173/295), grades III-IV in 9.8% (29/295), and grade V in 0.3% (1/295). In 20% (58/295), additional surgical procedures were needed. Grade III-V complications were associated with ≥ 4 cycles of preoperative chemotherapy (OR 3.7 (1.5-8.9); p = 0.004), RPLND specimen (nonseminoma or immature teratoma) (OR 3.1 (1.4-6.6); p = 0.005), transfusions (OR 2.4 (1.1-5.4); p = 0.03), salvage RPLND (OR 4.1 (1.8-9.3); p < 0.001), and preoperatively elevated AFP (OR 5 (2.2-11.7); p < 0.001). In multivariate analysis, the only independent predictor for grade III-V complications was preoperative AFP elevation (OR 3.3 (1.2-9.2); p = 0.02). Limitations include the retrospective study design. CONCLUSIONS: Our results demonstrate that RPLND is a demanding surgical procedure. Patients with a complex tumour history have a higher risk of complications. We recommend treatment of these complex cases in high-volume centres.
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Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Masculino , Humanos , Neoplasias Testiculares/patologia , Estudos Retrospectivos , alfa-Fetoproteínas/uso terapêutico , Espaço Retroperitoneal/cirurgia , Excisão de Linfonodo/métodos , Neoplasias Embrionárias de Células Germinativas/cirurgia , Complicações Pós-Operatórias/etiologiaRESUMO
Renal cell carcinoma (RCC) is the third most common urological tumor and has an extremely poor prognosis after metastasis has occurred. Therapeutic options are highly restricted, primarily due to resistance to classical chemotherapeutics. The development of new, innovative therapeutic procedures is thus of great urgency. In the present study, the influence of non-invasive physical plasma (NIPP) on malignant and non-malignant renal cells is characterized. The biological efficacy of NIPP has been demonstrated in malignant renal cell lines (786-O, Caki-1) and non-malignant primary human renal epithelial cells (HREpC). The cell responses that were experimentally examined were cell growth (cell number determination, calculation of growth rate and doubling time), cell motility (scratch assay, invasiveness assay), membrane integrity (uptake of fluorescent dye, ATP release), and induction of apoptosis (TUNEL assay, caspase-3/7 assay, comet assay). A single NIPP treatment of the malignant cells significantly inhibited cell proliferation, invasiveness, and metastasis. This treatment has been attributed to the disruption of membrane functionality and the induction of apoptotic mechanisms. Comparison of NIPP sensitivity of malignant 786-O and Caki-1 cells with non-malignant HREpC cells showed significant differences. Our results suggest that renal cancer cells are significantly more sensitive to NIPP than non-malignant renal cells. Treatment with NIPP could represent a promising innovative option for the therapy of RCC and might supplement established treatment procedures. Of high clinical relevance would be the chemo-sensitizing properties of NIPP, which could potentially allow a combination of NIPP treatment with low-dose chemotherapy.
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Metabolic reprogramming has been recognised as a hallmark in solid tumours. Malignant modification of the tumour's bioenergetics provides energy for tumour growth and progression. Otto Warburg first reported these metabolic and biochemical changes in 1927. In prostate cancer (PCa) epithelial cells, the tumour metabolism also changes during development and progress. These alterations are partly driven by the androgen receptor, the key regulator in PCa development, progress, and survival. In contrast to other epithelial cells of different entities, glycolytic metabolism in prostate cells sustains physiological citrate secretion in the normal prostatic epithelium. In the early stages of PCa, citrate is utilised to power oxidative phosphorylation and fuel lipogenesis, enabling tumour growth and progression. In advanced and incurable castration-resistant PCa, a metabolic shift towards choline, amino acid, and glycolytic metabolism fueling tumour growth and progression has been described. Therefore, even if the metabolic changes are not fully understood, the altered metabolism during tumour progression may provide opportunities for novel therapeutic strategies, especially in advanced PCa stages. This review focuses on the main differences in PCa's metabolism during tumourigenesis and progression highlighting glutamine's role in PCa.
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Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Próstata/patologia , Metabolismo Energético , Glicólise , Citratos/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
Immune checkpoint inhibitors have become a promising new therapy for cancer treatment. However, due to prostate cancer's high heterogeneity and immune-suppressive tumour microenvironment, clinical trials with immune checkpoint inhibitors for prostate cancer resulted in low or no response. This descriptive and retrospective study investigates the influence of androgen deprivation therapy (ADT) on PD-L1 expression and CD8+ T-cell tumour infiltration and activity in primary prostate cancer tissue. Therefore, immunohistochemistry was used to assess PD-L1, CD8+ T-cell, and the immune activation marker Granzyme B (GrB) in PCa tissue before and under ADT. In line with previous studies, few prostate cancer tissues showed PD-L1 expression and CD8+ T-cell infiltration. However, PD-L1 expression levels on tumour cells or infiltrating immune cells above 5% generated an immune-suppressive tumour microenvironment harbouring hypofunctional CD8+ T-cells. Moreover, analysis of a longitudinal patient cohort before and under ADT revealed that ADT increased hypofunctional CD8+ T cells in the tumour area suggesting a tumour immune milieu optimal for targeting with immunotherapy.
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The androgen receptor (AR) plays a central role in prostate, muscle, bone and adipose tissue. Moreover, dysregulated AR activity is a driving force in prostate cancer (PCa) initiation and progression. Consequently, antagonizing AR signalling cascades via antiandrogenic therapy is a crucial treatment option in PCa management. Besides, very high androgen levels also inhibit PCa cells' growth, so this effect could also be applied in PCa therapy. However, on the molecular and cellular level, these mechanisms have hardly been investigated so far. Therefore, the present study describes the effects of varying androgen concentrations on the viability of PCa cells as well as localization, transactivation, and protein stability of the AR. For this purpose, cell viability was determined via WST1 assay. Alterations in AR transactivity were detected by qPCR analysis of AR target genes. A fluorescent AR fusion protein was used to analyse AR localization microscopically. Changes in AR protein expression were detected by Western blot. Our results showed that high androgen concentrations reduce the cell viability in LNCaP and C4-2 cell lines. In addition, androgens have been reported to increase AR transactivity, AR localization, and AR protein expression levels. However, high androgen levels did not reduce these parameters. Furthermore, this study revealed an androgen-induced increase in AR protein synthesis. In conclusion, inhibitory effects on cell viability by high androgen levels are due to AR downstream signalling or non-genomic AR activity. Moreover, hormonal activation of the AR leads to a self-induced stabilization of the receptor, resulting in increased AR activity. Therefore, in clinical use, a therapeutic reduction in androgen levels represents a clinical target and would lead to a decrease in AR activity and, thus, AR-driven PCa progression.
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BACKGROUND/AIM: Heat shock proteins (HSP) play a crucial role in the cellular responses during stressful conditions. In addition, HSP are involved in the regulation of a variety of important signaling pathways and processes as well as many pathological conditions, including cancer. In prostate cancer (PC), HSP60 is associated with poor differentiation and prognostic clinical parameters, such as high Gleason score, initial serum prostate-specific antigen levels, and lower cancer-specific survival. In this study, we investigated the regulation of HSP60 protein in PC. MATERIALS AND METHODS: LNCaP or PC3 cells were treated with androgens or transfected with vectors containing microRNA-1 (miR-1), HSP60, HSP60-specific short-hairpin RNA (shHSP60), or a miR-1 inhibitor. The change in HSP60 protein levels was examined using Western blot. RESULTS: Treatment of PC cells with androgens did not alter the HSP60 protein levels. Modulation of miR-1 levels in LNCaP cells also did not affect the HSP60 protein. Furthermore, HSP60 levels could not be modified by overexpression or short hairpin RNA. CONCLUSION: It was found that neither physiological factors, such as androgens and the HSP60-specific miR-1, nor overexpression and knockdown systems could influence the HSP60 protein levels. These results suggest an essential role of HSP60 in PC cells, as its protein expression status is regulated very precisely.
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Chaperonina 60 , MicroRNAs , Proteínas Mitocondriais , Neoplasias da Próstata , Chaperonina 60/genética , Chaperonina 60/metabolismo , Proteínas de Choque Térmico/genética , Humanos , Masculino , MicroRNAs/genética , Células PC-3 , Próstata/patologia , Neoplasias da Próstata/patologiaRESUMO
Novel therapeutic strategies are urgently needed for advanced metastatic prostate cancer (PCa). Phytochemicals used in Traditional Chinese Medicine seem to exhibit tumor suppressive properties. Therefore, the therapeutic potential of artesunate (ART) on the progressive growth of therapy-sensitive (parental) and docetaxel (DX)-resistant PCa cells was investigated. Parental and DX-resistant PCa cell lines DU145, PC3, and LNCaP were incubated with artesunate (ART) [1-100 µM]. ART-untreated and 'non-cancerous' cells served as controls. Cell growth, proliferation, cell cycle progression, cell death and the expression of involved proteins were evaluated. ART, dose- and time-dependently, significantly restricted cell growth and proliferation of parental and DX-resistant PCa cells, but not of 'normal, non-cancerous' cells. ART-induced growth and proliferation inhibition was accompanied by G0/G1 phase arrest and down-regulation of cell cycle activating proteins in all DX-resistant PCa cells and parental LNCaP. In the parental and DX-resistant PC3 and LNCaP cell lines, ART also promoted apoptotic cell death. Ferroptosis was exclusively induced by ART in parental and DX-resistant DU145 cells by increasing reactive oxygen species (ROS). The anti-cancer activity displayed by ART took effect in all three PCa cell lines, but through different mechanisms of action. Thus, in advanced PCa, ART may hold promise as a complementary treatment together with conventional therapy.
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Signal Transducer and Activator of Transcription (STAT) proteins have been identified as drivers of prostate cancer (PCa) progression and development of aggressive castration-resistant phenotypes. In particular, STAT3, 5, and 6 have been linked to resistance to androgen receptor inhibition and metastasis in in vitro and in vivo models. This descriptive study aimed to validate these preclinical data in tissue obtained from patients with PCa before and while under androgen-deprivation therapy. Therefore, STAT3, 5, and 6 expressions and activity were assessed by immunohistochemistry. The data revealed that STAT3 and 5 changed in PCa. However, there was no relationship between expression and survival. Moreover, due to the heterogeneous nature of PCa, the preclinical results could not be transferred congruently to the patient's material. A pilot study with a longitudinal patient cohort could also show this heterogeneous influence of systemic therapy on STAT3, 5, and 6 expressions and activity. Even if the main mechanisms were validated, these data demonstrate the urge for better patient-near preclinical models. Therefore, these data reflect the need for investigations of STAT proteins in a longitudinal patient cohort to identify factors responsible for the diverse influence of system therapy on STAT expression.
RESUMO
Prostate-specific membrane antigen (PSMA) is an essential molecular regulator of prostate cancer (PCa) progression coded by the FOLH1 gene. The PSMA protein has become an important factor in metastatic PCa diagnosis and radioligand therapy. However, low PSMA expression is suggested to be a resistance mechanism to PSMA-based imaging and therapy. Clinical studies revealed that androgen receptor (AR) inhibition increases PSMA expression. The mechanism has not yet been elucidated. Therefore, this study investigated the effect of activation and inhibition of androgen signaling on PSMA expression levels in vitro and compared these findings with PSMA levels in PCa patients receiving systemic therapy. To this end, LAPC4, LNCaP, and C4-2 PCa cells were treated with various concentrations of the synthetic androgen R1881 and antiandrogens. Changes in FOLH1 mRNA were determined using qPCR. Open access databases were used for ChIP-Seq and tissue expression analysis. Changes in PSMA protein were determined using western blot. For PSMA staining in patients' specimens, immunohistochemistry (IHC) was performed. Results revealed that treatment with the synthetic androgen R1881 led to decreased FOLH1 mRNA and PSMA protein. This effect was partially reversed by antiandrogen treatment. However, AR ChIP-Seq analysis revealed no canonical AR binding sites in the regulatory elements of the FOLH1 gene. IHC analysis indicated that androgen deprivation only resulted in increased PSMA expression in patients with low PSMA levels. The data demonstrate that AR activation and inhibition affects PSMA protein levels via a possible non-canonical mechanism. Moreover, analysis of PCa tissue reveals that low PSMA expression rates may be mandatory to increase PSMA by androgen deprivation.