Development Of Prostate Cancer Research Articles

Research progress on the role of lipoxygenase and its inhibitors in prostate cancer.

Prostate cancer (PCa) has become a common disease among middle-aged and elderly men. The lipoxygenase (LOX) pathway plays a crucial role in the occurrence, development, invasion and metastasis of PCa and is therefore considered a new target for the prevention and treatment of PCa. 5-LOX and 12-LOX have a promoting effect on the occurrence, development, invasion and metastasis of PCa. 15-LOX-2 has an inhibitory effect on PCa. LOX inhibitors can effectively inhibit the metabolic activity of LOX. The research aims to review the mechanism of action and inhibitors of LOX in PCa, in order to provide relevant references for the prevention and treatment of PCa.

Unveiling RACK1: a key regulator of the PI3K/AKT pathway in prostate cancer development.

The dysregulated PI3K/AKT pathway is pivotal in the onset and progression of various cancers, including prostate cancer. However, targeting this pathway directly poses challenges due to compensatory upregulation of alternative oncogenic pathways. This study focuses on the novel regulatory activity of the Receptor for Activated Protein Kinase (RACK1), a scaffolding/adaptor protein, in governing the PI3K/AKT pathway within prostate cancer. Through a genetic mouse model, our research unveils RACK1's pivotal role in orchestrating AKT activation and the genesis of prostate cancer. RACK1 deficiency hampers AKT activation, effectively impeding prostate tumor formation induced by PTEN and p53 deficiency. Mechanistically, RACK1 facilitates AKT membrane translocation and fosters its interaction with mTORC2, thereby promoting AKT activation and subsequent tumor cell proliferation and tumor formation. Notably, inhibiting AKT activation via RACK1 deficiency does not trigger feedback upregulation of HER3 and androgen receptor (AR) expression and activation, distinguishing it from direct PI3K or AKT targeting. These findings position RACK1 as a critical regulator of the PI3K/AKT pathway and a promising target for curtailing prostate cancer development arising from pathway aberrations.

Glucose Upregulates ChREBP via Phosphorylation of AKT and AMPK to Modulate MALT1 and WISP1 Expression.

Glucose can activate the carbohydrate response element binding protein (ChREBP) transcription factor to control gene expressions in the metabolic pathways. The way of ChREBP involvement in human prostate cancer development remains undetermined. This study examined the interactions between prostate fibroblasts and cancer cells under the influences of ChREBP. Results showed that high glucose (30 mM) increased the phosphorylation of AKT at S473 and AMP-activated protein kinase (AMPK) at S485 in human prostate fibroblast (HPrF) cells and prostate cancer PC-3 cells. High glucose enhanced the expression of ChREBP, which increased the expressions of fibronectin, alpha-smooth muscle actin (α-SMA), and WNT1 inducible signaling pathway protein 1 (WISP1), magnifying the cell growth and contraction in HPrF cells in vitro. The cell proliferation, invasion, and tumor growth in prostate cancer PC-3 cells were enhanced by inducing the expressions of ChREBP, mucosa-associated lymphoid tissue 1 (MALT1), and epithelial-mesenchymal transition markers with high glucose treatment. Moreover, ectopic ChREBP overexpression induced NF-κB signaling activities via upregulating MALT1 expression in PC-3 cells. Our findings illustrated that ChREBP is an oncogene in the human prostate. High glucose condition induces a glucose/ChREBP/MALT1/NF-κB axis which links the glucose metabolism to the NF-κB activation in prostate cancer cells, and a glucose/ChREBP/WISP1 axis mediating autocrine and paracrine signaling between fibroblasts and cancer cells to promote cell migration, contraction, growth, and invasion of the human prostate.

Activation of Hedgehog pathway by circEEF2/miR-625-5p/TRPM2 axis promotes prostate cancer cell proliferation through mitochondrial stress.

The purpose of this study was to identify the role played by circEEF2 (has-circ-0048559) in prostate cancer (PCa) development and to determine the potential mechanism involved. circEEF2, miR-625-5p, and the transient receptor potential M2 channel protein (TRPM2) were determined using RT-qPCR in PCa. Cell proliferation was determined by CCK-8 assay and colony formation assay, whereas migration and invasion were assessed by Transwell assay, and apoptosis was evaluated by flow cytometry after annexin V-FITC and propidium iodide staining. The interactions between circEEF2 and miRNAs were investigated through the Circular RNA Interactome database, and the downstream targets of miR-625-5p were forecasted using TargetScan. The interaction was confirmed using both the dual luciferase reporter gene assay and RNA pull-down assay. TRPM2, Hedgehog signaling pathway proteins (GLI1 and GLI2), ubiquinone oxidase subunit B8, and cytochrome C oxidase subunit IV (COX4) were analyzed by protein blotting. JC-1 fluorescence detection was applied for mitochondrial membrane potential changes, fluorescent probe assay for intracellular ROS levels, and immunofluorescence staining for γ-H2AX expression. The role of circEEF2 in PCa tumor growth was tested by xenograft experiments. CircEEF2 expression was upregulated in PCa (p<0.05). Cells of PCa were inhibited in proliferation, migration, invasion, and enhanced in apoptosis by depleting circEEF2 (p<0.05). circEEF2 directly targeted adsorbed miR-625-5p. TRPM2 bound to miR-625-5p. Upregulating TRPM2 likewise reversed the therapeutic effect of depleting circEEF2 on cancer development in PCa cells. circEEF2 activated the Hedgehog pathway through the miR-625-5p/TRPM2 axis, promotes mitochondrial stress, and promotes PCa development in vivo. circEEF2 upregulates mitochondrial stress to promote PCa by activating the Hedgehog pathway through the miR-625-5p/TRPM2 axis.

PSTAT3 Expression is Increased in Advanced Prostate Cancer in Post-Initiation of Androgen Deprivation Therapy.

The transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) plays a role in carcinogenesis and is involved in processes, such as proliferation, differentiation, drug resistance and immunosuppression. STAT3 can be activated by phosphorylation of tyrosine at position 705 (pSTAT3Tyr705) or serine at 727 (pSTAT3Ser727). High expression levels of pSTAT3 are implicated in advanced stages of prostate cancer (PCa) and are known to interact with the androgen receptor signaling pathway. However, not much is known about how androgen deprivation therapy (ADT) in advanced disease affects pSTAT3 expression. The aim of this study was to determine the influence of ADT on pSTAT3 expression in PCa tissue. The study cohort came from a PCa tissue microarray resource containing prostate specimens from patients before and post-initiation of ADT. Tissue samples from 111 patients were immunostained for pSTAT3Tyr705 and pSTAT3Ser727. H-score was used to evaluate the intensity and the percentage of pSTAT3 expression in malignant epithelial and stromal compartments. Univariate and multivariable Cox regression analyses were used to assess pSTAT3Tyr705 and pSTAT3Ser727 as biomarkers of oncological outcome in patients undergoing ADT. Post-ADT PCa samples demonstrated increased nuclear and cytoplasmic levels of pSTAT3Ser727 in the stroma compared to pre-ADT samples, whereas pSTAT3Tyr705 expression was increased significantly in both stromal and malignant epithelial compartments except for stromal cytoplasm. High cytoplasmic pSTAT3Ser727 in stromal compartments correlated with reduced overall survival, shorter time to castration-resistant PCa development, and decreased metastasis-free survival. An increase in nuclear and cytoplasmic pSTAT3Ser727 expression within the stromal compartment of post-ADT samples corresponded to a shorter time to CRPC development, which was not observed for pSTAT3Tyr705. Multivariable survival analysis using Cox's regression identified that high cytoplasmic pSTAT3Ser727 expression in the stroma of post-ADT samples and pT3 or pT4-stage were associated with worse overall survival and 5-year metastasis-free survival (MFS). This study presents novel insights into the impact of ADT on the expression levels of pSTAT3Tyr705 and pSTAT3Ser727 in PCa. Cytoplasmic pSTAT3Ser727 status of cancer-associated stromal cells in post-ADT samples may serve as an independent prognostic marker for OS and 5-year MFS, identifying prostate cancer patients prone to developing resistance to ADT.

N-Acetylated Monosaccharides and Derived Glycan Structures Occurring in N- and O-Glycans During Prostate Cancer Development

Post-translational modifications of proteins play an important role in their stability, solubility and in vivo function. Also, for several reasons, such as the Golgi fragmentation during cancerogenesis, glycosylation as the most common modification is especially promising in offering high cancer specificity which, in combination with tissue-specific biomarkers available in the case of prostate diseases (PSA, PSMA, PAP), may lead to the development of novel oncodiagnostic approaches. In this review, we present the importance of subterminal glycan structures based on the N-acetylated monosaccharides GlcNAc and GalNAc in N- and also O-glycans, structures of which they are a component (LacNAc, LacdiNAc, branched structures). We also discuss the importance and clinical performance of these structures in cases of prostate cancer diagnostics using lectin-based affinity methods, which could be implemented in clinical laboratory practice in the future.

Epigenetic regulation of neuroendocrine prostate cancer

Neuroendocrine prostate cancer (PCa), an aggressive subtype of PCa, can arise de novo or from pre-existing castration-resistant PCa, especially after treatment with new-generation androgen receptor signaling inhibitors (ARSIs); thus, it is a major cause of resistance to ARSIs. Lineage plasticity drives the transformation of adenocarcinoma cells from the androgen receptor-driven luminal cell program to an alternative neuroendocrine transdifferentiation phenotype, which has been recognized as a key mechanism in neuroendocrine PCa development. Although genetic alterations can promote lineage plasticity, this process is primarily orchestrated through epigenetic regulation, including DNA methylation, chromatin modifications, and long noncoding RNA. Notably, epigenetic regulators are amenable therapeutic targets, offering the potential not only to address lineage plasticity but, more crucially, also to overcome resistance to ARSIs in PCa. In this review, we aim to elucidate the pivotal epigenetic factors driving the plasticity of the PCa lineage, providing a foundation for the development of treatment strategies to effectively combat resistance to ARSIs driven by lineage plasticity.

CORRELATION OF Trichomonas vaginalis INFECTION AND PROSTATE CANCER: A SYSTEMATIC REVIEW

Introduction: The presence of T. vaginalis in men should be investigated in terms of its ability to trigger inflammatory reactions and tissue changes capable of damaging the prostatic tissue. Objective: To assess whether there is a correlation between T. vaginalis infection and the risk of developing prostate cancer through systematic investigation. Methodology: To obtain the original studies, crosses were made between the descriptors in Health Sciences and Free Terms, in English and Portuguese, in the databases without limitation for the year of publication. Result: Of the nine articles used, four indicate the association of T. vaginalis infection with developing a malignant prostatic tumor. However, we emphasize the lack of studies with larger population groups and more specific and sensitive methodologies. Conclusion: We emphasize that seven articles were conducted with men residing in the United States, therefore, studies with the male population of other countries are fundamental for a better understanding of the association of T. vaginalis infection with the development of prostate cancer.

Structural insights into human ELAC2 as a tRNA 3' processing enzyme.

Human elaC ribonuclease Z 2 (ELAC2) removes the 3' trailer of precursor transfer ribonucleic acid (pre-tRNA). Mutations in ELAC2 are highly associated with the development of prostate cancer and hypertrophic cardiomyopathy. However, the catalytic mechanism of ELAC2 remains unclear. We determined the cryogenic electron microscopy structures of human ELAC2 in various states, including the apo, pre-tRNA-bound and tRNA-bound states, which enabled us to identify the structural basis for its binding to pre-tRNA and cleavage of the 3' trailer. Notably, conformational rearrangement of the C-terminal helix was related to feeding of the 3' trailer into the cleavage site, possibly explaining why its mutations are associated with disease. We further used biochemical assays to analyse the structural effects of disease-related mutations of human ELAC2. Collectively, our data provide a comprehensive structural basis for how ELAC2 recruits pre-tRNA via its flexible arm domain and guides the 3' trailer of pre-tRNA into the active centre for cleavage by its C-terminal helix.

P105 Prostate-specific membrane antigen positron emission tomography/computed tomography maximum standardized uptake values as a predictor for development of castration resistant prostate cancer in patients with biochemical recurrence after radical prostatectomy

P105 Prostate-specific membrane antigen positron emission tomography/computed tomography maximum standardized uptake values as a predictor for development of castration resistant prostate cancer in patients with biochemical recurrence after radical prostatectomy

Prostate-Specific Antigen Stratification for Predicting Advanced Prostate Cancer Events in Men Approaching Age Limits for Recommended Screening.

Our goal was to quantify the ability of various PSA values in predicting the likelihood of developing metastatic or fatal prostate cancer in older men. We used a random sample of patients in the US Veterans Health Administration to identify 80,706 men who had received PSA testing between ages 70 to 75. Our primary end point was time to development of either metastatic prostate cancer or death from prostate cancer. We used cumulative/dynamic modeling to account for competing events (death from non-prostate cancer causes) in studying both the discriminative ability of PSA as well as for positive predictive value and negative predictive value at 3 time points. PSA demonstrated time-dependent predictive discrimination, with receiver operating characteristic area under the curve at 5, 10, and 14 years decreasing from 0.83 to 0.77 to 0.73, respectively, but without statistically significant difference when stratified by race. At PSA thresholds between 1 and 8 ng/mL, the positive predictive value of developing advanced prostate cancer was significantly greater in Black than White patients. For instance, at a PSA > 3, at 5, 10, and 14 years, White patients had 2.4%, 2.9%, and 3.7% risk of an event, whereas Black patients had 4.3%, 6.5%, and 8.3% risk. In men aged 70 to 75 deciding whether to cease PSA testing with borderline-elevated PSA values, the risk of developing metastatic or fatal prostate cancer is quantifiable and relatively low. Risk assessment in this setting must account for the higher incidence of prostate cancer in Black men.

PI3K/Akt inhibition promotes AR activity and prostate cancer cell proliferation through p35-CDK5 modulation

Aberrant PI3K/Akt activation is linked to prostate cancer (PCa) malignancy, while androgen receptor (AR) is critical in early-stage PCa development. Investigating the interaction between these pathways is crucial for PCa malignancy. Our previous study demonstrated that p35-CDK5 mediates post-translational modifications of AR, STAT3, and p21CIP1, eventually promoting PCa cell growth. This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the β-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade.

Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment

BackgroundProstate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood.MethodsTo investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses.ResultsGenetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor.ConclusionsOur findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.

The relationship between immune cells and prostate cancer, and the mediating role of metabolites: a Mendelian randomization study

Research has demonstrated the significant involvement of immune cells in the development and progression of prostate cancer (PCa). However, the precise causal relationship between immune cells and PCa remains unclear. This study utilized bidirectional Mendelian randomization (MR) analysis to investigate the causal link between immune cells and PCa. Additionally, employed mediation MR design to ascertain the potential mediating role of metabolites in the connection between immune cells and PCa outcomes. Unswitched memory B cell % lymphocyte and CD24 + CD27 + B cell % lymphocyte were positively related to PCa risk, while CD62L − monocyte absolute count and CD62L − monocyte % monocyte were negatively associated with PCa risk. Sensitivity analysis was conducted to validate these results. The mediation MR results indicate that 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) levels may be an independent risk factor for PCa, while the succinate to acetoacetate ratio (SA ratio) was found to be a mediator for the effect of CD62L − monocyte % monocyte on PCa, with a mediation proportion of 16.6% (mediation percentage: 16.6%, 95%CI − 163% − 196%). The research validates the genetic causality between particular immune cells and PCa, and has emphasized the potential intermediary function of SA ratio. These noteworthy discoveries provide fresh perspectives for the clinical management of PCa.

Advances in Prostate Cancer Immunotherapy: Current Options and Emerging Novel Approaches

Prostate cancer (PCa) is a significant malignancy in men, contributing considerably to the rise in male mortality rates worldwide. Men diagnosed with PCa may have either localized or advanced stages of the disease. Globally, it ranks as the second most common and fifth most aggressive cancer type in males. The likelihood of developing prostate cancer in a man’s lifetime is approximately one in seven. Epidemiological research has linked various environmental and genetic factors to the abnormal growth of prostate cells, which leads to the formation of cancerous cells. Men experiencing a recurrence of prostate cancer or presenting with metastasis typically undergo androgen deprivation therapy (ADT), along with salvage radiotherapy and chemotherapy. While current treatment methods are more effective when used in combination, prostate cancer remains incurable. Research efforts are focused on exploring alternative treatments, including traditional medicine, nanotechnology applications, and gene therapy, to address drug resistance and mitigate the side effects associated with existing treatments. This article provides an overview the current treatment methods, and ongoing research into new treatment alternatives.

Comprehensive cataloging of miR-363 as a therapeutic & non-invasive biomarker of prostate cancer.

Background & objectives Overcoming the challenge of early diagnosis of prostate cancer (PCa) by exploring molecular biomarkers is urgently needed. With this objective, this study was designed to explore the biomarker and therapeutic potential of miRNA (miR)-363-3p in PCa pathogenesis. Methods Total participants (n=188) were enrolled, and blood and tissue samples were collected from individuals categorized into the control group (n=55), benign prostate hyperplasia (BPH) group (n=60), PCa group (n=48), and castration-resistant PCa (CRPC) group (n=25). MiR expression profiling was carried out using quantitative polymerase chain reaction (qPCR), and biomarker analysis was conducted employing receiver operating characteristics (ROC) curve. The miR-363 target genes were predicted by in silico tools like Target Scan and starBasev 2.0 and its expression was validated by qPCR and association among them was established by using the STRING database. Results The results showed that the tumour-suppressive nature of miR-363-3p in both PCa tissues and serum were significantly higher than the control with a greater area under curve (AUC) was 0.969 (sensitivity: 85%; specificity 100%) and 0.988 (sensitivity: 97.5%; specificity: 87.5%), respectively. The targetome analysis of miR-363-3p revealed five target genes-NRAS, E2F3, PTEN, MDM2, and CCNE2 which were strongly associated with cell division and proliferation. The expression analysis of the target genes showed a significant tumour-suppression of PTEN gene and significant upregulation of oncogenic genes such as NRAS, E2F3, MDM2, and CCNE2. Interpretation & conclusions Collectively, the findings of this study suggest that miR-363-3p may be a potential biomarker in differentiating individuals with PCa and CRPC from healthy controls. The miR-363-3p triggers various oncogenic genes (MDM2, NRAS, E2F3, CCNE2) and tumour suppressor genes (PTEN) that are actively involved in PCa progression and development.

Research Progress of AR Gene Family in Prostate Cancer Therapy

Prostate cancer (PCa) is a malignancy originating from the epithelial cells of the prostate gland, strongly influenced by androgens, and is one of the most common cancers in men. Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer. However, after prolonged ADT treatment, nearly all patients experience an increase in prostate-specific antigen (PSA) levels and tumor regrowth. The regrowth is primarily driven by the reactivation of androgen signaling pathways within the tumor cells, leading to the development of castration-resistant prostate cancer (CRPC). The overall survival for patients with CRPC is typically less than two years. The reactivation of androgen signaling after ADT is a key mechanism leading to the progression of CRPC. In particular, abnormal expression of androgen receptor (AR) family genes, particularly AKR1C3 and AR-V7, are beleived to play central roles in the emergence of CRPC. Beyond hormonal factors, various molecular mechanisms contribute to the development of castration resistance, such as genetic mutations and the role of the tumor microenvironment. Additionally, dysregulation of signaling pathways and interactions between tumor cells and the surrounding matrix furrher promote tumor survival and growth, even in the absence of androgens. Understanding these mechanisms is essential for developing more effective treatment strategies for CRPC.

Phase Separation Mediated Sub-Nuclear Compartmentalization of Androgen Receptors.

The androgen receptor (AR), a member of the nuclear steroid hormone receptor family of transcription factors, plays a crucial role not only in the development of the male phenotype but also in the development and growth of prostate cancer. While AR structure and AR interactions with coregulators and chromatin have been studied in detail, improving our understanding of AR function in gene transcription regulation, the spatio-temporal organization and the role of microscopically discernible AR foci in the nucleus are still underexplored. This review delves into the molecular mechanisms underlying AR foci formation, focusing on liquid-liquid phase separation and its role in spatially organizing ARs and their binding partners within the nucleus at transcription sites, as well as the influence of 3D-genome organization on AR-mediated gene transcription.

Integrated analysis of single-cell RNA-seq and bulk RNA-seq revealed key genes for bone metastasis and chemoresistance in prostate cancer.

Prostate cancer (PCa) is a serious malignancy. The main causes of PCa aggravation and death are unexplained resistance to chemotherapy and bone metastases. This study aimed to investigate the molecular mechanisms associated with the dynamic processes of progression, bone metastasis, and chemoresistance in PCa. Through comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data, Gene Expression Omnibus (GEO) tumor progression and metastasis-related genes were identified. These genes were subjected to lasso regression modeling using the Cancer Genome Atlas (TCGA) database. Tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative PCR (RT-qPCR) were used to evaluate osteoclast differentiation. CellMiner was used to confirm the effect of LDHA on chemoresistance. Finally, the relationship between LDHA and chemoresistance was verified using doxorubicin-resistant PCa cell lines. 7928 genes were identified as genes related to tumor progression and metastasis. Of these, 7 genes were found to be associated with PCa prognosis. The scRNA-seq and TCGA data showed that the expression of LDHA was higher in tumors and associated with poor prognosis of PCa. In addition, upregulation of LDHA in PCa cells induces osteoclast differentiation. Additionally, high LDHA expression was associated with resistance to Epirubicin, Elliptinium acetate, and doxorubicin. Cellular experiments demonstrated that LDHA knockdown inhibited doxorubicin resistance in PCa cells. LDHA may play a potential contributory role in PCa initiation and development, bone metastasis, and chemoresistance. LDHA is a key target for the treatment of PCa.

Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second-leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. Here, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared to their castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer (CSPC) populations, the obligate sGC heterodimer was repressed via methylation of its beta subunit. Genetically abrogating sGC complex formation in CSPC cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and co-treatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell-intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy.