Therapeutic Target For Prostate Cancer Research Articles

Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer.

Prostate-specific membrane antigen (PSMA) is an important cell-surface imaging biomarker and therapeutic target in prostate cancer. The PSMA-targeted theranostic 177Lu-PSMA-617 was approved in 2022 for men with PSMA-PET-positive metastatic castration-resistant prostate cancer. However, not all patients respond to PSMA-radioligand therapy, in part owing to the heterogeneity of PSMA expression in the tumour. The PSMA regulatory network is composed of a PSMA transcription complex, an upstream enhancer that loops to the FOLH1 (PSMA) gene promoter, intergenic enhancers and differentially methylated regions. Our understanding of the PSMA regulatory network and the mechanisms underlying PSMA suppression is evolving. Clinically, molecular imaging provides a unique window into PSMA dynamics that occur on therapy and with disease progression, although challenges arise owing to the limited resolution of PET. PSMA regulation and heterogeneity - including intertumoural and inter-patient heterogeneity, temporal changes, lineage dynamics and the tumour microenvironment - affect PSMA theranostics. PSMA response and resistance to radioligand therapy are mediated by a number of potential mechanisms, and complementary biomarkers beyond PSMA are under development. Understanding the biological determinants of cell surface target regulation and heterogeneity can inform precision medicine approaches to PSMA theranostics as well as other emerging therapies.

Casein Kinase 1α—A Target for Prostate Cancer Therapy?

The androgen receptor (AR) is a key driver of prostate cancer (PCa) and, as such, current mainstay treatments target this molecule. However, resistance commonly arises to these therapies and, therefore, additional targets must be evaluated to improve patient outcomes. Consequently, alternative approaches for indirectly targeting the AR are sought. AR crosstalk with other signalling pathways, including several protein kinase signalling cascades, has been identified as a potential route to combat therapy resistance. The casein kinase 1 (CK1) family of protein kinases phosphorylate a multitude of substrates, allowing them to regulate a diverse range of pathways from the cell cycle to DNA damage repair. As well as its role in several signalling pathways that are de-regulated in PCa, mutational data suggest its potential to promote prostate carcinogenesis. CK1α is one isoform predicted to regulate AR activity via phosphorylation and has been implicated in the progression of several other cancer types. In this review, we explore how the normal biological function of CK1 is de-regulated in cancer, the impact on signalling pathways and how this contributes towards prostate tumourigenesis, with a particular focus on the CK1α isoform as a novel therapeutic target for PCa.

USP47 deficiency in mice modulates tumor infiltrating immune cells and enhances antitumor immune responses in prostate cancer

This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.

Integrating single-cell RNA-sequencing and bulk RNA-sequencing data to explore the role of mitophagy-related genes in prostate cancer

Prostate cancer (PCa) is the most common malignancy of the male urinary system. Mitophagy, as a type of autophagy, can remove damaged mitochondria in cells. Mitophagy-related genes (MRGs) have been shown to play critical roles in the development of PCa. To this end, based on the comprehensive analysis of RNA-seq and scRNA-seq data of PCa samples and their controls, this paper identified PCa subtypes and constructed a prognostic model. In this paper, we downloaded scRNA-seq and RNA-seq data from Gene Expression Omnibus (GEO) and TCGA database. Based on the R package “Seurat” to process the scRNA-seq data, a total of five cell types were identified. Each cell population was scored based on the R package “AUCell” and using the intersection genes between MRGs and each cell population. The B cell population was then identified as a high-scoring cell population. Differentially expressed genes in RNA-seq data were identified based on the R package “limma” and intersected with previously intersected genes. Then, based on univariate Cox regression analysis and Lasso-Cox regression analysis, the prognostic genes were screened, and the risk model was constructed (composed of ADH5, CAT, BCAT2, DCXR, OGT, and FUS). The model is validated on internal and external test sets. Independent prognostic analysis identified age, N stage, and risk score as independent prognostic factors. This paper's risk models and prognostic genes can provide a reference for developing novel therapeutic targets for PCa.

Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition.

Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death. We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.

Exploration of vitamin D metabolic activity-related biological effects and corresponding therapeutic targets in prostate cancer

BackgroundPrevious studies have unequivocally demonstrated that the vitamin D (VD) metabolism pathway significantly influences prognosis and sensitivity to hormone therapy in prostate cancer (PCa). However, the precise underlying mechanism remains unclear.MethodsWe performed molecular profiling of 1045 PCa patients, leveraging genes linked to VD synthesis and VD receptors. We then identified highly variable gene modules with substantial associations with patient stratification. Subsequently, we intersected these modules with differentially expressed genes between PCa and adjacent paracancerous tissues. Following a meticulous process involving single-factor regression and LASSO regression to eliminate extraneous variables and construct a prognostic model. Within the high-risk subgroup defined by the calculated risk score, we analyzed their differences in cell infiltration, immune status, mutation landscape, and drug sensitivity. Finally, we selected Apolipoprotein E (APOE), which featured prominently in this model for further experimental exploration to evaluate its potential as a therapeutic target.ResultsThe prognostic model established in this study had commendable predictive efficacy. We observed diminished infiltration of various T-cell subtypes and reduced expression of co-stimulatory signals from antigen-presenting cells. Mutation analysis revealed that the high-risk cohort harbored a higher frequency of mutations in the TP53 and FOXA genes. Notably, drug sensitivity analysis suggested the heightened responsiveness of high-risk patients to molecular inhibitors targeting the Bcl-2 and MAPK pathways. Finally, our investigation also confirmed that APOE upregulates the proliferative and invasive capacity of PCa cells and concurrently enhances resistance to androgen receptor antagonist therapy.ConclusionThis comprehensive study elucidated the potential mechanisms through which this metabolic pathway orchestrates the biological behavior of PCa and findings hold promise in advancing the development of combination therapies in PCa.

NCAPD3 exerts tumor-promoting effects in prostatic cancer via dual impact on miR-30a-5p by STAT3-MALAT1 and MYC

Non-SMC condensin II complex subunit D3 (NCAPD3) is a subunit of the non-structural maintenance of chromosomes condensin II complex, which involves chromosome condensation and segregation during mitosis. NCAPD3 has recently been demonstrated as a crucial oncogenic factor. However, the underlying mechanism of NCAPD3 in prostate cancer (PCa) remains not completely clear. In this study, we confirmed that lncRNA MALAT1 was induced by NCAPD3-STAT3, and the expression of miR-30a-5p was controlled by NCAPD3 in PCa cells by miRNA-seq. Through quantitative real-time PCR, fluorescence in situ hybridization, western blotting, and immunohistochemistry assay, we demonstrated that miR-30a-5p was lowly expressed in PCa cells and tissues compared to the controls, which was contrary to NCAPD3 expression and markedly downregulated by NCAPD3. Then, MALAT1 was analyzed for the complementary sequence in the potential interaction with miR-30a-5p by using the predicted target module of public databases. Dual-luciferase reporter assay and RNA immunoprecipitation were carried out to verify that MALAT1 functioned as a sponge for miR-30a-5p to reduce miR-30a-5p expression. Meanwhile, MYC acted as a transcriptional repressor to directly bind the promoter of the miR-30a-5p located gene and repress the miR-30a-5p expression. Furthermore, the upregulation of NCAPD3 on cell viability and migration was significantly attenuated in PC-3 cells when miR-30a-5p was overexpressed. NCAPD3 overexpression also accelerated tumor growth in the xenograft mouse model and repressed miR-30-5p. In summary, this work elucidates NCAPD3 inhibits miR-30a-5p through two pathways: increasing STAT3-MALAT1 to sponge miR-30a-5p and increasing MYC to directly inhibit miR-30a-5p transcription, which could serve as potential therapeutic targets for prostate cancer.

Abstract 5577: TRPM8 mediated Ca2+ signaling as a therapeutic target in prostate cancer

Abstract Prostate cancer (PC) is a prevalent and deadly malignancy, necessitating the development of innovative therapeutic strategies. Transient receptor potential melastatin 8 (TRPM8), an ion channel highly expressed in prostate epithelium, has emerged as a potential target. Our preliminary studies demonstrate that TRPM8 plays a crucial role in PC progression. We observed an initial increase in TRPM8 mRNA expression during early-stage PC, followed by a decline in advanced and androgen-independent prostate cancer (AIPC) stages. Additionally, TRPM8 knockout mice exhibited elevated serum testosterone levels, heightened androgen receptor (AR) activity, and increased cell cycle, invasion, and adhesion-related effects. In xenograft models, TRPM8 demonstrated potent antitumor properties in both AR+ and AR- contexts. Our research suggests that TRPM8 activation on the plasma membrane promotes calcium influx and induces apoptosis in PC cells. Conversely, TRPM8 internalization correlates with PC pathogenesis. By exploring the effects of TRPM8 on PTEN-mediated cellular signaling, we aim to uncover novel insights into the molecular mechanisms underlying TRPM8's role in PC. This abstract underscores the potential of targeting TRPM8-mediated Ca2+ signaling as a promising therapeutic approach to combat PC progression, offering hope for improved patient outcomes. Citation Format: Swapna Asuthkar, Kiran Velpula, Vander Don Griend. TRPM8 mediated Ca2+ signaling as a therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5577.

Abstract 462: Developing the miR-888 cluster as a therapeutic target for prostate cancer

Abstract Prostate Cancer (PCa) is a serious health crisis in the United States. 20% of men diagnosed with PCa will progress to fast-growing, advanced disease. There are no curative treatment options for PCa that has spread to distant sites and the 5-year survival rate for metastatic disease remains 30%. Recognizing the need for better PCa therapeutics, we are developing novel anti-microRNA delivery reagents targeted against the noncoding RNA miR-888 cluster to block prostate tumor progression. Our lab identified these oncomiRs in a biomarker discovery screen as elevated in human metastatic PCa cell lines and prostatic fluids from patients with high-grade PCa. We noted that over-expression of miR-888 cluster members (miR-888, miR-891a) promoted prostate cell growth and induced invasiveness in vitro. miR-888 and miR-891a also accelerated xenograft tumor growth in mice. Treatment of aggressive PCa cells in culture with synthetic antisense inhibitors against individual cluster members reversed these growth and invasion phenotypes, highlighting their clinical potential. We are testing pH Low Insertion Peptide (pHLIP)-Peptide Nucleic Acid (PNA)-based antimiR conjugates against miR-888 and miR-891a. The delivery vehicle pHLIP is a 36-amino acid peptide that at low pH (< pH 6.5) adopts an alpha-helical conformational change and facilitates the insertion of its C-terminus across lipid bilayers to transport conjugated anti-miRNA cargo into cells. When administered systemically, pHLIP effectively targets solid tumors with acidic microenvironments. We found that these reagents are readily internalized by human PCa cells cultured at pH 6.0 and in prostate xenograft tumors when delivered systemically in mice. Treatment significantly repressed miR-888 and miR-891a and acted to slow prostate cell growth in vitro. We are currently moving these studies into mouse prostate models. Furthermore, we are investigating the downstream signaling pathways for the miR-888 cluster. Our work indicates that the miR-888 cluster network coordinates the repression of the Tissue Inhibitors of Metalloproteinase (TIMP) and SMAD4 anti-metastatic pathways to drive extracellular matrix degradation and prostate cell invasion, and as a consequence, induces matrix metalloproteinase (MMP) activity. Expression profiling arrays and luciferase reporter assays indicated that multiple members of the miR-888 cluster co-suppress TIMPs in the prostate and similarly elevate multiple MMPs as well as cadherins, fibronectin and heparinase, and co-modulated several immune response genes. We are currently studying the consequence of various CRISPR-mediated miR-888 cluster deletions to understand how this non-coding RNA cluster functionally overlaps to promote aggressive PCa. This work will establish new clinical tools for aggressive PCa and optimize patient treatment management. Citation Format: Katherine Routon, Trevor Fachko, Vishal Kasina, Raman Bahal, Aurora Esquela Kerscher. Developing the miR-888 cluster as a therapeutic target for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 462.

Abstract 6048: Targeting AR positive prostate cancer cells by the novel P300/CBP oral available PROTAC degrader

Abstract Background The Androgen Receptor (AR) serves as the core lineage-specific transcription factor for prostatic epithelial cells. Targeting AR is currently the most promising therapeutic strategy. However, the inevitable development of acquired resistance to anti-androgen treatments underscores the urgent need to devise new therapeutic strategies. Recent studies have revealed that in prostate cancer cells, AR is hijacked by oncogenic transcription factors, such as FOXA1 and HOXB13, which promiscuously bind to distinct enhancer sites, driving the progression of prostate cancer. This process leads to the formation of a substantially rewired AR cancer specific enhanceosome, requiring a variety of coregulators to exhibit oncogenic driver characteristics, which can be potential therapeutic targets for prostate cancer. Histone acetyltransferases (HATs) P300 and CBP are paralogs which play dominant roles in orchestrating high-order chromatin structures and transcription factor complexes by acetylating histone proteins at multiple residuals. Although accumulating evidence suggests that P300/CBP function as AR coregulator and targeting P300/CBP can markedly suppress AR-positive prostate cancer cell growth, including growth of castration-resistant prostate cancer (CRPC), most of the P300/CBP inhibitors have performed poorly in clinical trials. Methods We developed a novel P300/CBP dual oral available PROTAC degrader, namely CBPD-409. The on-target effects of CBPD-409 were assessed by quantitative proteomics (TMT-mass spectrometry) in prostate cancer cell lines. The RNA-seq analysis was conducted to investigate CBPD-409 effects on global transcriptome in prostate cancer cells. The cytotoxicity of CBPD-409 in multiple prostate cancer cell lines was examined by cell-titer-glo and incucyte assays. Conclusion In multiple cell lines, CBPD-409 exhibits remarked potency to degrade both P300 and CBP proteins in time and does dependent manner, without evident off-target effects. By employing CBPD-409, we demonstrate that degrading P300/CBP preferentially suppress AR+ prostate cancer cell growth. The global transcriptomic profiling in CBPD-409 treated prostate cancer cells revealed that loss of P300/CBP results in remarkedly downregulation of AR, Myc, FOXA1 and ERG signaling. Assessment of CBPD-409 cytotoxicity in a panel prostate cancer cell lines suggests that AR positive prostate cancer cells display highest sensitivity to CBPD-409. Citation Format: Jie luo, Abhijit Prolia, Yuanyuan Qiao, Jean Tian, Rahul Mannan, Somnath Mahapatra, Zhixiang Chen, Rithvik Seri, Shaomeng Wang, Arul Chinnaiyan. Targeting AR positive prostate cancer cells by the novel P300/CBP oral available PROTAC degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6048.

Abstract 3007: AZGP1 inhibits angiogenesis in prostate cancer

Abstract AZGP1 is involved in various biological processes, including lipid metabolism, regulation of cell proliferation, migration and invasion, and immune response. The loss of AZGP1 is associated with worse clinical outcomes, and AZGP1 has been indicated as a potential biomarker for prostate cancer. However, the underlying mechanisms of AZGP1 function in prostate cancer are unknown. This study reports AZGP1's pivotal involvement in angiogenesis within the prostate cancer tumor environment. Neither knockout nor overexpression of AZGP1 affects in vitro prostate cancer cell proliferation, migration, or invasion. Morphologically, AZGP1-deficient mouse prostates appear normal, but exhibit increased fibroblast growth in periglandular stroma after 6 months. The overexpression of AZGP1 does not impact the growth of PC3 and DU145 tumors; instead, these tumors significantly reduced microvessel density, suggesting AZGP1 exhibits anti-angiogenic properties. Proteomic profiling shows distinct profile of angiogenesis-related proteins between PC3-AZGP1-OV and PC3 control cells, featuring proteins like PDCD6 and MMP9. This study provides insights into the anti-angiogenic attributes of AZGP1 in prostate cancer, underscoring its potential as a therapeutic target for prostate cancer. Citation Format: Ru Wen, G Edward Wen, Zhengyuan Qiu, Eric E Peterson, Fernando Jose Garcia Marques, Abel Bermudez, Jonathan R Pollack, Hongjuan Zhao, Sharon Pitteri, James Brooks. AZGP1 inhibits angiogenesis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3007.

A Signal-Finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration-Resistant Prostate Cancer: Results from CYCLONE 1.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC). Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%. At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib. Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.

Thermal Proteome Profiling Strategy Identifies CNPY3 as a Cellular Target of Gambogic Acid for Inducing Prostate Cancer Pyroptosis.

There is an urgent requirement to acquire a comprehensive comprehension of novel therapeutic targets for prostate cancer to facilitate the development of medications with innovative mechanisms. In this study, we identified gambogic acid (GBA) as a specific pyroptosis inducer in prostatic cancer cells. By using a thermal proteome profiling (TPP) strategy, we revealed that GBA induces pyroptosis by directly targeting the canopy FGF signaling regulator (CNPY3), which was previously considered "undruggable". Moreover, through the utilization of the APEX2-based proximity labeling method, we found that GBA recruited delactatease SIRT1, resulting in the elimination of lysine lactylation (Kla) on CNPY3. Of note, SIRT1-mediated delactylation influenced the cellular localization of CNPY3 to promote lysosome rupture for triggering pyroptosis. Taken together, our study identified CNPY3 as a distinctive cellular target for pyroptosis induction and its potential application in prostate cancer therapy.

Single-cell RNA combined with bulk RNA analysis to explore oxidative stress and energy metabolism factors and found a new prostate cancer oncogene MXRA8.

Prostate cancer is the most common malignancy among men worldwide, and its diagnosis and treatment are challenging due to its heterogeneity. Integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, we identified two molecular subtypes of prostate cancer based on dysregulated genes involved in oxidative stress and energy metabolism. We constructed a risk score model (OMR) using common differentially expressed genes, which effectively evaluated prostate cancer prognosis. Our analysis demonstrated a significant correlation between the risk score model and various factors, including tumor immune microenvironment, genomic variations, chemotherapy resistance, and immune response. Notably, patients with low-risk scores exhibited increased sensitivity to chemotherapy and immunotherapy compared to those with high-risk scores, indicating the model's potential to predict patient response to treatment. Additionally, our investigation of MXRA8 in prostate cancer showed significant upregulation of this gene in the disease as confirmed by PCR and immunohistochemistry. Functional assays including CCK-8, transwell, plate cloning, and ROS generation assay demonstrated that depletion of MXRA8 reduced the proliferative, invasive, migratory capabilities of PC-3 cells, as well as their ROS generation capacity. Our study highlights the potential of oxidative stress and energy metabolism-related genes as prognostic markers and therapeutic targets in prostate cancer. The integration of scRNA-seq and bulk RNA-seq data enables a better understanding of prostate cancer heterogeneity and promotes personalized treatment development. Additionally, we identified a novel oncogene MXRA8 in prostate cancer.

Association between circulating immune cells and the risk of prostate cancer: a Mendelian randomization study.

There is still limited research on the association between immune cells and the risk of prostate cancer. Further investigations are warranted to comprehend the intricate associations at play. We used a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between immune cell phenotypes and prostate cancer. The summary data for immune cell phenotypes was derived from a study cohort, including 3,757 individuals from Sardinia with data on 731 immune cell phenotypes. The summary data for prostate cancer were obtained from the UK Biobank database. Sensitivity analyses were conducted, and the combination of MR-Egger and MR-Presso was used to assess horizontal pleiotropy. Cochran's Q test was employed to evaluate heterogeneity, and the results were subjected to FDR correction. Our study identified two immune cell phenotypes significantly associated with the risk of prostate cancer, namely CD25 on naive-mature B cells (OR = 0.998, 95% CI, 0.997-0.999, P = 2.33E-05, FDR = 0.017) and HLA DR on CD14- CD16- cells (OR = 1.001, 95% CI, 1.000-1.002, P = 8.01E-05, FDR = 0.03). When adjusting FDR to 0.2, we additionally found six immune cell phenotypes influencing the incidence of prostate cancer. These include FSC-A on B cells (OR = 1.002, 95% CI, 1.001-1.002, P = 7.77E-04, FDR = 0.133), HLA DR on plasmacytoid dendritic cells (OR = 1.001, 95% CI, 1.000-1.001, P = 0.001, FDR = 0.133), CD14+ CD16- monocyte % monocytes (OR = 1.002, 95% CI, 1.001-1.003, P = 0.001, FDR = 0.133), and HVEM on effector memory CD4+ T cells (OR = 1.001, 95% CI, 1.000-1.002, P = 0.002, FDR = 0.169), which are positively correlated with the risk of prostate cancer. Conversely, CD25 on IgD+ B cells (OR = 0.998, 95% CI, 0.997-0.999, P = 0.002, FDR = 0.169) and Monocytic Myeloid-Derived Suppressor Cells AC (OR = 0.999, 95% CI, 0.999-1.000, P = 0.002, FDR = 0.17) are negatively correlated with the risk of prostate cancer. This study has revealed causal relationships between immune cell phenotypes and prostate cancer, supplying novel insights that might aid in identifying potential therapeutic targets of prostate cancer.

Harnessing tumor-derived exosomes: A promising approach for the expansion of clinical diagnosis, prognosis, and therapeutic outcome of prostate cancer.

Prostate cancer is the second leading cause of men's death worldwide. Although early diagnosis and therapy for localized prostate cancer have improved, the majority of men with metastatic disease die from prostate cancer annually. Therefore, identification of the cellular-molecular mechanisms underlying the progression of prostate cancer is essential for overcoming controlled proliferation, invasion, and metastasis. Exosomes are small extracellular vesicles that mediate most cells' interactions and contain membrane proteins, cytosolic and nuclear proteins, extracellular matrix proteins, lipids, metabolites, and nucleic acids. Exosomes play an essential role in paracrine pathways, potentially influencing Prostate cancer progression through a wide variety of mechanisms. In the present review, we outline and discuss recent progress in our understanding of the role of exosomes in the Prostate cancer microenvironment, like their involvement in prostate cancer occurrence, progression, angiogenesis, epithelial-mesenchymal transition, metastasis, and drug resistance. We also present the latest findings regarding the function of exosomes as biomarkers, direct therapeutic targets in prostate cancer, and the challenges and advantages associated with using exosomes as natural carriers and in exosome-based immunotherapy. These findings are a promising avenue for the expansion of potential clinical approaches.

EDNRB inhibits the growth and migration of prostate cancer cells by activating the cGMP-PKG pathway.

Prostate cancer (PCa) represents a substantial global health concern and a prominent contributor to male cancer-related mortality. The aim of this study is to explore the role of B-type endothelin receptor (EDNRB) in PCa and evaluate its therapeutic potential. The investigation employed predictive methodologies encompassing data acquisition from the GEO and TCGA databases, gene screening, enrichment analysis, in vitro experiments involving PCR, Western blotting, wound healing, and Transwell assays, as well as animal experiments. Analysis revealed a significant downregulation of EDNRB expression in PCa cells. Overexpression of EDNRB demonstrated inhibitory effects on tumor cell growth, migration, and invasion, likely mediated through activation of the cGMP-Protein Kinase G pathway. In vivo experiments further confirmed the tumor-suppressive properties of EDNRB overexpression. These findings underscore the prospect of EDNRB as a therapeutic target for PCa, offering novel avenues for PCa treatment strategies.

Extracellular vesicles related gene HSPH1 exerts anti-tumor effects in prostate cancer via promoting the stress response of CD8 + T cells.

T cell stress response state (TSTR), as a novel immune concept previous studies have proposed, has not yet been explored in prostate cancer (PC). As a type of cellular efflux, exosomes play important roles in the occurrence and development of PC. Here, we conducted a combined analysis on extracellular vesicle related genes (EVRGs) in PC using data from single-cell RNA (scRNA), spatial transcriptome (ST), and bulk RNA sequencing. Preliminary findings have revealed that heat shock protein family H (Hsp110) member 1 (HSPH1) possesses two identities, one being EVRGs and the other being a member of the heat shock protein family involved in TSTR, which may promote the differentiation of conventional T cells towards Th1 or Th2 cells through the pathway of IL2-MYC-IL2RA, thereby promoting the increase of CD8 + T cells in the tumor area, especially in the invasive zone, and inhibiting the invasion of PCs. We also notice the negative response of HSPH1 + CD8 + T cell related genes in immune checkpoint blockade (ICB). Western blot (WB) and droplet digital Polymerase Chain Reaction (ddPCR) demonstrated that the mRNA and protein levels of HSPH1 in EVs of PCs were significantly higher than those in adjacent tissues. Results above indicate the potential of HSPH1 as a critical therapeutic target in PC.

NCAPG2 promotes prostate cancer malignancy and stemness via STAT3/c-MYC signaling.

Prostate cancer (PCa) is the second leading cause of cancer-related mortality among men worldwide, and its incidence has risen substantially in recent years. Therefore, there is an urgent need to identify novel biomarkers and precise therapeutic targets for managing PCa progression and recurrence. We investigated the clinical significance of NCAPG2 in PCa by exploring public datasets and our tissue microarray. Receiver operating characteristic (ROC) curve and survival analyses were performed to evaluate the correlation between NCAPG2 and PCa progression. Cell proliferation, wound healing, transwell, flow cytometry, cell cycle, tumor sphere formation, immunofluorescence (IF), co-immunoprecipitation (co-IP), and chromatin immunoprecipitation (ChIP) assays were conducted to further elucidate the molecular mechanism of NCAPG2 in PCa. Subcutaneous and orthotopic xenograft models were applied to investigate the effects of NCAPG2 on PCa proliferation in vivo. Tandem mass tag (TMT) quantitative proteomics was utilized to detect proteomic changes under NCAPG2 overexpression. NCAPG2 was significantly upregulated in PCa, and its overexpression was associated with PCa progression and unfavorable prognosis. Knockdown of NCAPG2 inhibited the malignant behavior of PCa cells, whereas its overexpression promoted PCa aggressiveness. NCAPG2 depletion attenuated the development and growth of PCa in vivo. TMT quantitative proteomics analyses indicated that c-MYC activity was strongly correlated with NCAPG2 expression. The malignancy-promoting effect of NCAPG2 in PCa was mediated via c-MYC. NCAPG2 could directly bind to STAT3 and induce STAT3 occupancy on the MYC promoter, thus to transcriptionally activate c-MYC expression. Finally, we identified that NCAPG2 was positively correlated with cancer stem cell (CSC) markers and enhanced self-renewal capacity of PCa cells. NCAPG2 is highly expressed in PCa, and its level is significantly associated with PCa prognosis. NCAPG2 promotes PCa malignancy and drives cancer stemness via the STAT3/c-MYC signaling axis, highlighting its potential as a therapeutic target for PCa.

Androgen-repressed lncRNA LINC01126 drives castration-resistant prostate cancer by regulating the switch between O-GlcNAcylation and phosphorylation of androgen receptor.

Prostate cancer (PCa) initially shows satisfactory response to therapies targeting the androgen receptor (AR). However, progression to a castration-resistant stage indicates poor prognosis in PCa patients. AR signalling still plays a central role in most castration-resistant prostate cancers (CRPC). Therefore, unveiling the mechanisms of AR reactivation under androgen-deprived conditions is imperative to discover novel therapeutic targets for CRPC. Using an integrative analysis of the transcriptomics of three independent PCa cohorts and a published landscape of AR-regulated long non-coding RNA (lncRNA), lncRNA LINC01126 was selected as a candidate gene that could drive CRPC progression for further study. Quantitative reverse transcription polymerase chain reaction, in situ hybridisation (ISH) and fluorescent ISH were performed to detect LINC01126 in PCa tissues and cells. The functional role and mechanism of LINC01126 were further investigated using in vitro and in vivo gain and loss of function assays. LINC01126, identified as an AR-repressed lncRNA, was significantly upregulated after AR-targeted therapies. In addition, we found that LINC01126 was upregulated in CRPC and was associated with poor prognosis. We also proved that LINC01126 stabilised AR protein and enhanced AR nuclear translocation and transactivation by promoting the transition from O-GlcNAcylation at threonine 80 to phosphorylation at serine 81 (S81) within the AR protein. Mechanism analysis revealed that LINC01126 facilitates the interaction of CDK9 with AR and impedes the binding of O-linked N-acetylglucosamine (O-GlcNAc) transferase to AR. Consequently, LINC01126 expression was sufficient to activate AR signalling without androgen. LINC01126 overexpression increased, whereas LINC01126 knockdown decreased castration resistance traits in PCa cells in vitro and in vivo. Furthermore, our data showed that LINC01126-targeting antisense oligonucleotides (ASO) substantially inhibited CRPC cells in vitro. Our research expands the functions of AR-regulated lncRNA in sustaining androgen-independent AR activity and promoting CRPC progression and reveals that LINC01126 may be a new therapeutic target for PCa.