Pathogenesis Of Prostate Cancer Research Articles

Role of N6‑methyladenosine in the pathogenesis, diagnosis and treatment of prostate cancer (Review).

Prostate cancer (PCa) affects males of all racial and ethnic groups, and leads to higher rates of mortality in those belonging to a lower socioeconomic status due to the late detection of the disease. PCa affects middle‑aged males between the ages of 45 and 60 years, and is the highest cause of cancer‑associated mortality in Western countries. As the most abundant and common mRNA modification in higher eukaryotes, N6‑methyladenosine (m6A) is widely distributed in mammalian cells and influences various aspects of mRNA metabolism. Recent studies have found that abnormal expression levels of various m6A regulators significantly affect the development and progression of various types of cancer, including PCa. The present review discusses the influence of m6A regulatory factors on the pathogenesis and progression of PCa through mRNA modification based on the current state of research on m6A methylation modification in PCa. It is considered that the treatment of PCa with micro‑molecular drugs that target the epigenetics of the m6A regulator to correct abnormal m6A modifications is a direction for future research into current diagnostic and therapeutic approaches for PCa.

Sphingolipids in prostate cancer prognosis: integrating single-cell and bulk sequencing.

Stratifying patient risk and exploring the tumor microenvironment are critical endeavors in prostate cancer research, essential for advancing our understanding and management of this disease. Single-cell sequencing data for prostate cancer were sourced from the pradcellatlas website, while bulk transcriptome data were obtained from the TCGA database. Dimensionality reduction cluster analysis was employed to investigate heterogeneity in single-cell sequencing data. Gene set enrichment analysis, utilizing GO and KEGG pathways, was conducted to explore functional aspects. Weighted gene coexpression network analysis (WGCNA) identified key gene modules. Prognostic models were developed using Cox regression and LASSO regression techniques, implemented in R software. Validation of key gene expression levels was performed via PCR assays. Through integrative analysis of single-cell and bulk transcriptome data, key genes implicated in prostate cancer pathogenesis were identified. A prognostic model focused on sphingolipid metabolism (SRSR) was constructed, comprising five genes: "FUS," "MARK3," "CHTOP," "ILF3," and "ARIH2." This model effectively stratified patients into high-risk and low-risk groups, with the high-risk cohort exhibiting significantly poorer prognoses. Furthermore, distinct differences in the immune microenvironment were observed between these groups. Validation of key gene expression, exemplified by ILF3, was confirmed through PCR analysis. This study contributes to our understanding of the role of sphingolipid metabolism in prostate cancer diagnosis and treatment. The identified prognostic model holds promise for improving risk stratification and patient outcomes in clinical settings.

Association between vitamin B2 intake and prostate-specific antigen in American men: 2003–2010 National Health and Nutrition Examination Survey

BackgroundAccumulating evidence suggests a pivotal role of vitamin B2 in the pathogenesis and progression of prostate cancer (PCa). Vitamin B2 intake has been postulated to modulate the screening rate for PCa by altering the concentration of prostate-specific antigen(PSA). However, the relationship between vitamin B2 and PSA remains indeterminate. Hence, we conducted a comprehensive evaluation of the association between vitamin B2 intake and PSA levels, utilizing data from the National Health and Nutrition Examination Survey (NHANES) database.MethodsFrom a pool of 20,371 participants in the NHANES survey conducted between 2003 and 2010, a cohort of 2,323 participants was selected for the present study. The male participants were classified into four distinct groups based on their levels of vitamin B2 intake. We employed a multiple linear regression model and a non-parametric regression method to investigate the relationship between vitamin B2 and PSA levels.ResultsThe study cohort comprised of 2,323 participants with a mean age of 54.95 years (± 11.73). Our findings revealed a statistically significant inverse correlation between vitamin B2 intake (mg) and PSA levels, with a reduction of 0.13 ng/ml PSA concentration for every unit increase in vitamin B2 intake. Furthermore, we employed a fully adjusted model to construct a smooth curve to explore the possible linear relationship between vitamin B2 intake and PSA concentration.ConclusionsOur study in American men has unveiled a notable inverse association between vitamin B2 intake and PSA levels, potentially posing a challenge for the identification of asymptomatic prostate cancer. Specifically, our findings suggest that individuals with higher vitamin B2 intake may be at a greater risk of being diagnosed with advanced prostate cancer in the future, possibly indicating a detection bias. These results may offer a novel explanation for the observed positive correlation between vitamin B2 intake and prostate cancer.

Prevalence of DNA-Repair Gene Mutations in Mexican Men with Prostate Cancer

Introduction and objectiveMexico reported 26,742 new cases of prostate cancer in 2020. Different risk factors have been identified in the pathogenesis of prostate cancer. Among them, genetic factors and alterations or mutations in specific genes have been described in different ethnic groups worldwide. The aim of our study is to report the prevalence of germline DNA-repair gene mutations in Mexican patients with prostate cancer. Material and methodWe performed germline genetic testing in 50 patients with localized prostate cancer and 50 patients with metastatic prostate cancer. Demographic, clinical, and histopathological data were collected. ResultsThirty-seven germline mutations were identified in 32 patients. The most commonly affected genes were ATM in 6%, followed by FANCA (5%), and ATR (4%). BRCA2 mutations were identified in 3%. The frequency of mutations was higher in the metastatic group. Discussion and ConclusionThe results of our study show different mutations from those reported in different populations or regions. The use of PARP inhibitors is indicated in patients with germline mutations, specifically BRCA2, showing improvement in overall survival and progression free survival. To our knowledge, this is the first study reporting the prevalence of mutations in DNA-repair genes in Mexican patients with prostate cancer.

Integrated grade-wise profiling analysis reveals potential plasma miR-373-3p as prognostic indicator in Prostate Cancer & its target KPNA2

BackgroundPlasma microRNAs (miRNAs) have recently garnered attention for their potential as stable biomarkers in the context of Prostate Cancer (PCa), demonstrating established associations with tumor grade, biochemical recurrence (BCR), and metastasis. This study seeks to assess the utility of plasma miRNAs as prognostic indicators for distinguishing between high-grade and low-grade PCa, and to explore their involvement in PCa pathogenesis. MethodologyWe conducted miRNA profiling in both plasma and tissue specimens from patients with varying PCa grades. Subsequently, the identified miRNAs were validated in a substantial independent PCa cohort. Furthermore, we identified and confirmed the gene targets of these selected miRNAs through Western blot analysis. ResultsIn our plasma profiling investigation, we identified 98, 132, and 154 differentially expressed miRNAs (DEMs) in high-grade PCa vs. benign prostatic hyperplasia (BPH), low-grade PCa vs. BPH, and high-grade PCa vs. low-grade PCa, respectively. Our tissue profiling study revealed 111, 132, and 257 statistically significant DEMs for the same comparisons. Notably, miR-373-3p emerged as the sole consistently dysregulated miRNA in both plasma and tissue samples of PCa. This miRNA displayed significant overexpression in plasma and tissue samples, with fold changes of 3.584 ± 0.5638 and 8.796 ± 1.245, respectively. Furthermore, we observed a significant reduction in KPNA2 protein expression in PCa. ConclusionOur findings lend support to the potential of plasma miR-373-3p as a valuable biomarker for predicting and diagnosing PCa. Additionally, this miRNA may contribute to the progression of PCa by inhibiting KPNA2 expression, shedding light on its role in the disease.

Prostate Tissue Microbiome in Patients with Prostate Cancer: A Systematic Review.

Some researchers have speculated that the prostatic microbiome is involved in the development of prostate cancer (PCa) but there is no consensus on certain microbiota in the prostatic tissue of PCa vs. healthy controls. This systematic review aims to investigate and compare the microbiome of PCa and healthy tissue to determine the microbial association with the pathogenesis of PCa. We searched MEDLINE, Embase, and Scopus databases. Articles were screened by two independent and blinded reviewers. Literature that compared the prostatic tissue microbiome of patients with PCa with benign controls was included. We found that PCa may be associated with increased Propionibacterium acnes, the herpesviridae and papillomaviridae families, and Mycoplasma genitalium, but definitive conclusions cannot be drawn from the existing data. Challenges include the difficulty of obtaining uncontaminated tissue samples and securing tissue from healthy controls. As a result, methods are varied with many studies using cancerous and "healthy" tissue from the same prostate. The organisms chosen for each study were also highly variable, making it difficult to compare studies. These issues have led to lower confidence in our results. Overall, further work is warranted to better understand the implications of the prostatic microbiome in the pathogenesis of PCa.

Transcription Factors in Prostate Cancer: Insights for Disease Development and Diagnostic and Therapeutic Approaches.

Transcription factors (TFs) are proteins essential for the regulation of gene expression, and they regulate the genes involved in different cellular processes, such as proliferation, differentiation, survival, and apoptosis. Although their expression is essential in normal physiological conditions, abnormal regulation of TFs plays critical role in several diseases, including cancer. In prostate cancer, the most common malignancy in men, TFs are known to play crucial roles in the initiation, progression, and resistance to therapy of the disease. Understanding the interplay between these TFs and their downstream targets provides insights into the molecular basis of prostate cancer pathogenesis. In this review, we discuss the involvement of key TFs, including the E26 Transformation-Specific (ETS) Family (ERG and SPDEF), NF-κB, Activating Protein-1 (AP-1), MYC, and androgen receptor (AR), in prostate cancer while focusing on the molecular mechanisms involved in prostate cancer development. We also discuss emerging diagnostic strategies, early detection, and risk stratification using TFs. Furthermore, we explore the development of therapeutic interventions targeting TF pathways, including the use of small molecule inhibitors, gene therapies, and immunotherapies, aimed at disrupting oncogenic TF signaling and improving patient outcomes. Understanding the complex regulation of TFs in prostate cancer provides valuable insights into disease biology, which ultimately may lead to advancing precision approaches for patients.

Prevalencia de mutaciones en genes de reparación en hombres mexicanos con cáncer de próstata

Introduction and objectiveMexico reported 26,742 new cases of prostate cancer in 2020. Different risk factors have been identified in the pathogenesis of prostate cancer. Among them, genetic factors and alterations or mutations in specific genes have been described in different ethnic groups worldwide. The aim of our study is to report the prevalence of germline DNA-repair gene mutations in Mexican patients with prostate cancer. Material and methodWe performed germline genetic testing in 50 patients with localized prostate cancer and 50 patients with metastatic prostate cancer. Demographic, clinical, and histopathological data were collected. ResultsThirty-seven germline mutations were identified in 32 patients. The most commonly affected genes were ATM in 6%, followed by FANCA (5%), and ATR (4%). BRCA2 mutations were identified in 3%. The frequency of mutations was higher in the metastatic group. Discussion and ConclusionThe results of our study show different mutations from those reported in different populations or regions. The use of PARP inhibitors is indicated in patients with germline mutations, specifically BRCA2, showing improvement in overall survival and progression free survival. To our knowledge, this is the first study reporting the prevalence of mutations in DNA-repair genes in Mexican patients with prostate cancer.

Knockdown of growth differentiation factor-15 restrains prostate cancer through regulating MAPK/ERK signaling pathway.

Prostate cancer, prevalent among males, is influenced by various molecular factors, including Growth Differentiation Factor 15 (GDF15). Despite its recognized role in multiple tumor types, GDF15's specific involvement in prostate cancer remains insufficiently explored. This study investigates the regulatory function of GDF15 in prostate cancer. To explore GDF15's impact, we established GDF15 knockdown and overexpression models in prostate cancer cells. We quantified mRNA and protein levels using RT-PCR and Western blotting. Functional assays, including CCK8, Transwell, wound healing, and flow cytometry, were employed to evaluate cell proliferation, invasion, migration, and apoptosis. Additionally, the effect of GDF15 on tumor growth was assessed using a metastatic tumor model in nude mice. Elevated GDF15 expression was identified in prostate cancer tissues and cells. The knockdown of GDF15 led to the activation of the MAPK/ERK signaling pathway. C16PAF was found to counteract the inhibitory effects of sh-GDF15 on cell proliferation, invasion, migration, and apoptosis in LNCaP cells. It also reversed the sh-GDF15-induced alterations in the epithelial-mesenchymal transition (EMT) process. In vivo, C16PAF notably mitigated the sh-GDF15-induced suppression of tumor growth. The study demonstrated that sh-GDF15 inhibits cell proliferation, invasion, migration, EMT process, and tumor growth, while it promotes apoptosis. However, these effects were significantly reversed by C16PAF. The study underscores the potential of GDF15 as a target for novel therapeutic interventions in prostate cancer treatment and prevention. These findings illuminate GDF15's multifaceted role in prostate cancer pathogenesis and suggest its viability as a therapeutic target.

Abstract 4437: Dysregulated lipid metabolism and high-fat diet influences prostate cancer (PCa) progression

Abstract Dysregulation of lipid metabolism is observed during the development and progression of various types of cancer including prostate cancer (PCa). Systemic metabolic changes driven by genetic alterations in conjunction with obesity and a high-fat diet have been demonstrated to induce PCa progression. In this study, we aimed to investigate the impact of high- and low-fat diets on the progression and morbidity of prostate cancer, utilizing inducible genetically engineered mouse models (GEMMs) that mimic different grades of prostate cancer. The mice were initially placed on a standard diet until week 6, after which they were randomly assigned to either a low-fat or high-fat diet. At week 8, the Cre recombinase enzyme was activated to induce the desired phenotype in the GEMMs, effectively mimicking the initiation and progression of prostate cancer. The experimental design allowed us to gain insights into the interplay between dysregulated lipid metabolism, diet, and the pathogenesis of prostate cancer. Two groups of mice were taken for the study, with one group being fed a low-fat diet and the other group being fed a high-fat diet. The mice were maintained on their respective diets for a period of 1, 3, and 5 months. At each endpoint, tissue samples were collected. Samples were taken from the prostate, plasma, and liver tissues. These samples were then subjected to various analyses to investigate the changes occurring at the molecular and cellular level. Blood was collected to determine lipidomic content in response to high and low-fat diet and the relation of tumour progression. Finally, faecal samples were collected throughout the duration of the experiment to perform metagenomic studies. The consumption of a high-fat diet significantly increased the body weight of the mice which corresponded to increased liver weight. Furthermore, we identified that the consumption of a high-fat diet significantly correlated with an increase in prostate weight at 3 and 5 months after initiation. Preliminary metabolomic analysis of the plasma revealed a distinct clustering of samples based on the consumed diet. Metagenomic analyses conducted at 1 and 3 months indicated a visible shift in the composition and diversity of gut microbiota in mice fed either a high- or low-fat diet. In conclusion, our study will shed light on the influence of dietary factors on prostate cancer development, providing valuable information for the development of targeted therapeutic strategies to combat this disease. Citation Format: Saurav Subedi, Federico La Manna, Katja Ovchinnikova, Eugenio Zoni, Nicola Zamboni, Bahtiyar Yilmaz, George N. Thalmann, Marianna Kruithof-de Julio. Dysregulated lipid metabolism and high-fat diet influences prostate cancer (PCa) progression [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 4437.

Abstract 5593: METTL3-NUP93 axis as a novel therapeutic target in castration-resistant prostate cancer (CRPC)

Abstract Androgens and androgen receptor (AR) are the key factors driving the development and progression of prostate cancer. Extensive studies confirm both androgens and AR are required for normal growth and development of the prostate gland, and also in prostate cancer pathogenesis and androgen-independent cancer progression. Therefore, androgen deprivation therapies or targeting AR function have always been the mainstay of therapeutic strategy against advanced prostate cancers. However, the current therapeutic strategies are temporally effective in suppressing prostate tumors, and eventually develop metastatic disease. Nuclear pore complex (NPC) is a large complex composed of approximately 30 different proteins termed nucleoporins (NUPs), which serve as the structural and functional units for macromolecules shuttling including proteins and messenger RNAs (mRNAs) between nucleus and cytoplasm. Abnormal expression or genetic alterations of NUP genes has been indicated to involve in the progression of prostate cancer, but the underlying molecular mechanisms are poorly understood. We recently found that the m6A methyltransferase METTL3 directly interacts with nucleoporin 93 (NUP93), one of the NPC components in multiple prostate cancer cells, which seems to be more robust in the castration-resistant prostate cancer (CRPC) cell lines. Disruption of METTL3-NUP93 axis abrogated proliferation and oncogenic phenotypes of CRPC cells, suggesting that the METTL3-NUP93 axis may play an important role in prostate cancer progression to castration resistance. Most importantly, a subgroup of mRNAs regulated through METTL3-NUP93 axis encode cholesterol biosynthesis enzymes that trigger the activation of persistent AR signaling in CRPC. Therefore, Our current findings suggest that inhibition of METTL3-NUP93 axis may represent a promising therapeutic strategy for CRPC, the lethal form of the disease. Citation Format: Jihoon Lee, Zhao Zhang, Juyeong Hong, Kexin Xu. METTL3-NUP93 axis as a novel therapeutic target in castration-resistant prostate cancer (CRPC) [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 5593.

Comparison of molecular analysis results determined by next-generation sequencing to immunohistochemical indicators and clinicopathological parameters in prostate adenocarcinomas.

Prostate cancer is a common cancer in males, frequently leading to mortality. Multiple genetic factors play roles in prostate cancer pathogenesis. Demonstration of pathological pathways and customised treatment options have been possible with next-generation sequencing. In this study, we aimed to evaluate the relationships of the changes in the prostate cancer pathways genes with the pathological, immunohistochemical and the clinical parameters. Retrospective cross-sectional study. Materials and Methods: Among the prostate needle biopsy materials investigated in Adnan Menderes University Faculty of Medicine, Department of Pathology, thirty-one cases, who had been analysed using the next-generation sequencing system, were included in this study. As a result of statistical analysis, a significant relationship was found between the pathogenic mutation detected in androgen receptor and Breast Cancer Gene 2 genes and tumour volume. In all cases with a pathogenic mutation in the androgen receptor gene, a pathogenic mutation in the Protein Tyrosine Phosphatase and Tensin Homolog gene was also observed and a significant relationship was found between them. Castration resistance was observed in cases with high tumour volume, and a statistically significant difference was found. A statistically significant relationship was found between tumour volume and Ki-67 expression. In addition, a significant relationship was observed between the castration resistance and Ki-67, c-erbB2 expressions. A statistically significant relationship was found between Ki-67 and c-erbB2. Regarding prognosis prediction and treatment, identifying the molecular changes in genes playing roles in prostate cancer with next-generation sequencing is very important.

Clinical assessment of TGFB1 and HP Relative Gene Expression in the Peripheral Blood of Prostate Cancer Patients.

This study aimed to assess the relative gene expression level of transforming growth factor-β1 (TGFB1) and haptoglobin (HP) in the peripheral blood of prostate cancer (PCa) patients and evaluate their diagnostic ability. A total of 125 participants were enrolled in the present study. Among them, 75 PCa patients, 25 benign prostatic hyperplasia (BPH) patients, and 25 healthy volunteers served as the control group. The relative TGFB1 and HP gene expression level was quantified using real-time polymerase chain reaction. Further, free and total PSA levels were determined using electrochemiluminescence assays. TGFB1 was significantly over-expressed, whereas HP was significantly downregulated in the peripheral blood of PCa patients compared to BPH and control groups (p-value ranges from 0.034 to <0.001). Moreover, the high expression level of TGFB1 was associated with an increased risk of PCa development with OR=1.412 (95%CI: 1.081-1.869, p= 0.012). TGFB1 and HP relative expression levels had lower diagnostic performance to differentiate PCa from normal and BPH individuals compared to PSA, however, the combination of the tested parameters improved the diagnostic efficacy. TGFB1 and HP relative expression have moderate diagnostic efficacy in discriminating patients with PCa from BPH and healthy subjects. Furthermore, over-expression of TGFB1 may contribute to the pathogenesis of PCa.

Heparin Oligosaccharides as Vasoactive Intestinal Peptide Inhibitors via their Binding Process Characterization.

It has been proven that vasoactive intestinal peptide (VIP) was involved in the pathogenesis of prostate cancer. Cardin et al. found that by an alanine scan, the heparin-binding site on VIP was exactly the same sequence in VIP and its receptor. Therefore, heparin could competitively block the binding of VIP and its receptor. However, the structure-activity relationship between heparin and VIP has not been reported, especially in terms of the sequence and sulfation patterns of heparin oligosaccharides upon binding to VIP. The binding process between heparin oligosaccharides and VIPA variety of experiments was designed to study the structure-activity relationship between heparin oligosaccharides and VIP. Heparin was enzymatically digested and purified to produce heparin oligosaccharides, and the structures were characterized by NMR. The binding capacity between heparin oligosaccharides and VIP was analyzed by GMSA and ITC experiments. The binding between heparin oligosaccharides and VIP was simulated using a molecular docking program to show the complex. ELISA assay was used to investigate the effect of non-anticoagulant heparin oligosaccharides on the VIP-mediated cAMP/PKA signaling pathway in vitro. The results indicated that both the length and the sulfation pattern of heparin oligosaccharides affected its binding to VIP. VIP could induce the expression of cAMP at a higher level in PC3 cells, which could be regulated by the interaction of heparin oligosaccharides and VIP. The binding between heparin oligosaccharides and VIP could block the binding between VIP and its receptor on tumor cells. Downloading the regulation of the expression level of cAMP could possibly further affect the subsequent activation of PKA. These non-anticoagulant heparin oligosaccharides may block the VIP-mediated cAMP/PKA signaling pathway and thus exert their antitumor activity.

Germline Mutations and Ancestry in Prostate Cancer.

Prostate cancer is the most frequently diagnosed non-cutaneous malignancy of men in the USA; notably, the incidence is higher among men of African, followed by European and Asian ancestry. Germline mutations and, in particular, mutations in DNA damage repair genes (DDRGs) have been implicated in the pathogenesis of prostate cancer. This review intends to discuss the implication of ancestry on prostate cancer, specifically in regard to lack of diversity in genomic and genetic databases and the ability of providers to properly counsel patients on the significance of cancer genetic results. Ancestral differences in prostate cancer-associated DDRG germline mutations are increasingly recognized. Guidelines for treatment by the National Comprehensive Cancer Network® (NCCN®) support germline testing in certain patients, and a myriad of genetic testing panels for DDRG mutations are now available in clinical practice. However, the consensus among providers on what genes and mutations to include in the genetic tests has evolved from experience from men of European ancestry (EA). Gaps in ancestry-informed clinical practice exist in genetic risk assessment, implementation of screening, counseling, guiding recommendations, treatment, and clinical trial enrollment. The lack of diversity in tumor genomic and genetic databases may hinder ancestry-specific disease-predisposing alterations from being discovered and targeted in prostate cancer and, therefore, impede the ability of providers to accurately counsel patients on the significance of cancer genetic test results.

CAMP-phosphodiesterase 4D7 (PDE4D7) forms a cAMP signalosome complex with DHX9 and is implicated in prostate cancer progression.

A robust body of work has demonstrated that a reduction in cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform 7 (PDE4D7) is linked with negative prostate cancer outcomes; however, the exact molecular mechanism that underpins this relationship is unknown. Epigenetic profiling has shown that the PDE4D gene can be hyper-methylated in transmembrane serine protease 2 (TMPRSS2)-ETS transcriptional regulator ERG (ERG) gene-fusion-positive prostate cancer (PCa) tumours, and this inhibits messenger RNA (mRNA) expression, leading to a paucity of cellular PDE4D7 protein. In an attempt to understand how the resulting aberrant cAMP signalling drives PCa growth, we immunopurified PDE4D7 and identified binding proteins by mass spectrometry. We used peptide array technology and proximity ligation assay to confirm binding between PDE4D7 and ATP-dependent RNA helicase A (DHX9), and in the design of a novel cell-permeable disruptor peptide that mimics the DHX9-binding region on PDE4D7. We discovered that PDE4D7 forms a signalling complex with the DExD/H-box RNA helicase DHX9. Importantly, disruption of the PDE4D7-DHX9 complex reduced proliferation of LNCaP cells, suggesting the complex is pro-tumorigenic. Additionally, we have identified a novel protein kinase A (PKA) phosphorylation site on DHX9 that is regulated by PDE4D7 association. In summary, we report the existence of a newly identified PDE4D7-DHX9 signalling complex that may be crucial in PCa pathogenesis and could represent a potential therapeutic target.

TLR9 Monotherapy in Immune-Competent Mice Suppresses Orthotopic Prostate Tumor Development.

Prostate cancer is ranked second in the world for cancer-related deaths in men, highlighting the lack of effective therapies for advanced-stage disease. Toll-like receptors (TLRs) and immunity have a direct role in prostate cancer pathogenesis, but TLR9 has been reported to contribute to both the progression and inhibition of prostate tumorigenesis. To further understand this apparent disparity, we have investigated the effect of TLR9 stimulation on prostate cancer progression in an immune-competent, syngeneic orthotopic mouse model of prostate cancer. Here, we utilized the class B synthetic agonist CPG-1668 to provoke a TLR9-mediated systemic immune response and demonstrate a significant impairment of prostate tumorigenesis. Untreated tumors contained a high abundance of immune-cell infiltrates. However, pharmacological activation of TLR9 resulted in smaller tumors containing significantly fewer M1 macrophages and T cells. TLR9 stimulation of tumor cells in vitro had no effect on cell viability or its downstream transcriptional targets, whereas stimulation in macrophages suppressed cancer cell growth via type I IFN. This suggests that the antitumorigenic effects of CPG-1668 were predominantly mediated by an antitumor immune response. This study demonstrated that systemic TLR9 stimulation negatively regulates prostate cancer tumorigenesis and highlights TLR9 agonists as a useful therapeutic for the treatment of prostate cancer.

From microbes to medicine: harnessing the gut microbiota to combat prostate cancer.

The gut microbiome (GM) has been identified as a crucial factor in the development and progression of various diseases, including cancer. In the case of prostate cancer, commensal bacteria and other microbes are found to be associated with its development. Recent studies have demonstrated that the human GM, including Bacteroides, Streptococcus, Bacteroides massiliensis, Faecalibacterium prausnitzii, Eubacterium rectale, and Mycoplasma genitalium, are involved in prostate cancer development through both direct and indirect interactions. However, the pathogenic mechanisms of these interactions are yet to be fully understood. Moreover, the microbiota influences systemic hormone levels and contributes to prostate cancer pathogenesis. Currently, it has been shown that supplementation of prebiotics or probiotics can modify the composition of GM and prevent the onset of prostate cancer. The microbiota can also affect drug metabolism and toxicity, which may improve the response to cancer treatment. The composition of the microbiome is crucial for therapeutic efficacy and a potential target for modulating treatment response. However, their clinical application is still limited. Additionally, GM-based cancer therapies face limitations due to the complexity and diversity of microbial composition, and the lack of standardized protocols for manipulating gut microbiota, such as optimal probiotic selection, treatment duration, and administration timing, hindering widespread use. Therefore, this review provides a comprehensive exploration of the GM's involvement in prostate cancer pathogenesis. We delve into the underlying mechanisms and discuss their potential implications for both therapeutic and diagnostic approaches in managing prostate cancer. Through this analysis, we offer valuable insights into the pivotal role of the microbiome in prostate cancer and its promising application in future clinical settings.

Silencing of matrix metalloprotease-12 delays the progression of castration-resistant prostate cancer by regulating autophagy and lipolysis.

The complex pathogenesis of castration-resistant prostate cancer (CRPC) makes it challenging to identify effective treatment methods. Matrix metalloproteinase (MMP)-12 can degrade elastin as well as various extracellular matrix (ECM) components, which is associated with cancer progression. However, the relationship between MMP-12 and CRPC progression is poorly understood. In this study, we observed the effect of MMP-12 on the progression of CRPC and further explored its potential mechanism of action. High levels of MMP-12 were observed in patients with CRPC. We therefore developed cell co-culture and mouse models to study the function of MMP-12. Silencing MMP-12 in CRPC cells disrupted lipid utilization and autophagy marker expression via the CD36/CPT1 and P62/LC3 pathways, respectively, leading to reduced CRPC cell migration and invasion. Moreover, animal experiments confirmed that MMP-12-knockdown CRPC xenograft tumors exhibited reduced tumor growth, and the mechanisms involved the promotion of cancer cell autophagy and the inhibition of lipid catabolism. According to our results, MMP-12 played important roles in the progression of CRPC by disrupting adipocyte maturation and regulating cancer migration and invasion via the modulation of autophagy and lipid catabolism pathways.

Unveiling the Anticancer Potential of Pasak Bumi (Eurycoma Longifolia Jack) Root Extract in Prostate Cancer Treatment.

Prostate cancer remains a significant global health concern, necessitating the exploration of novel therapeutic avenues to enhance treatment efficacy and mitigate adverse effects. Objective This study delves into the potential anticancer properties of Pasak Bumi (Eurycoma longifolia Jack) root extract, a traditional Southeast Asian medicinal plant, against prostate cancer. The research employs a multifaceted approach, encompassing molecular and cellular analyses to unravel the intricate mechanisms underlying Pasak Bumi's effects on prostate cancer cells. Primary focus is given to the PTEN/P13k/Akt pathway, a critical regulator of cell survival and apoptosis. Various concentrations of Pasak Bumi root extract are applied to prostate cancer cell lines, and the impact on apoptosis, cell proliferation, and key molecular targets is assessed. Preliminary findings reveal that Pasak Bumi root extract induces apoptosis in prostate cancer cells, evidenced by downstream molecular events associated with programmed cell death. The extract demonstrates concentration-dependent effects, with higher concentrations exhibiting more pronounced anticancer activity. Moreover, Pasak Bumi root extract appears to modulate the PTEN/P13k/Akt pathway, providing a potential mechanistic link to its anticancer effects. Discussion: The study's significance lies in its contribution to the evolving landscape of natural compounds as anticancer agents, particularly in the context of prostate cancer. Pasak Bumi's traditional use as a medicinal plant, coupled with emerging scientific evidence, underscores its potential translational value. The observed modulation of the PTEN/P13k/Akt pathway aligns with the current understanding of prostate cancer pathogenesis, offering a plausible explanation for Pasak Bumi's anticancer effects. This research sheds light on the promising anticancer potential of Pasak Bumi root extract against prostate cancer. Further exploration of its molecular interactions, synergy with conventional therapies, and efficacy at different stages of cancer progression is warranted. The findings present Pasak Bumi as a nature-inspired candidate for prostate cancer treatment, warranting continued investigation into its therapeutic applications. As the scientific community endeavors to enhance cancer treatment modalities, Pasak Bumi emerges as a captivating subject in the pursuit of effective and minimally invasive prostate cancer therapies.