Prostate Cancer Prevention Research Articles

Serum uric acid and prostate cancer: findings from the NHANES (2007–2020)

BackgroundThe relationship between serum uric acid (SUA) levels and prostate cancer (PCa) remains controversial. This cross-sectional study investigated the association between SUA levels and PCa incidence.MethodsA total of 9,776 participants aged ≥40 from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2020 were included, 503 of whom had PCa. Weighted univariate logistic regression, multivariate logistic regression, and smooth-fitting curve analyses were used to analyze the association between SUA and PCa incidence. Concurrently, the fitted smoothing curves were used to explore the potential non-linear relationships. If non-linearity was observed, a recursive algorithm further calculated the inflection point.ResultsThree models were used to analyze the correlation between SUA levels and PCa incidence. All regression models demonstrated a negative correlation between SUA levels and PCa incidence (model 1: OR = 0.88, 95% CI=0.80–0.97; model 2: OR = 0.87, 95% CI=0.80–0.96; model 3: OR = 0.87, 95% CI=0.78–0.96). According to the trend test, with increasing SUA, the risk of PCa showed a downward trend (three models P for trend = 0.037, 0.015, 0.016). According to the subgroup analysis, a significant negative correlation between SUA and PCa was detected in individuals aged >60 years, non-Hispanic whites, those of other races, and those with hypertension. Moreover, the association between SUA and PCa followed a U-shaped curve among participants without hypertension, and the inflection point of SUA was 5.1 mg/dl.ConclusionsThis cross-sectional study revealed a negative relationship between SUA levels and the risk of PCa, particularly in specific demographic groups. These findings offer a fresh perspective on the role of SUA in PCa patients, potentially paving the way for new approaches for the prevention and treatment of PCa. However, further studies are necessary to validate these findings.

Relationships of dietary habits with prostate cancer risk: results from Mendelian randomization analyses and the National Health and Nutrition Examination Survey.

Background: Prior investigations identified correlations between dietary habits and the risk of prostate cancer (PCa); however, the causative dynamics are unclear. Methods: Utilizing the Mendelian randomization (MR) framework, we investigated the causal links between dietary habits, daily nutrient intakes, and risk of PCa (79 148 cases and 61 106 controls). Exposure and outcome data were obtained from the UK Biobank and the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) consortium, respectively. Univariable and multivariable MR analyses were employed. Sensitivity analyses were performed to detect outliers, evaluate heterogeneity, and discern potential pleiotropic effects. Utilizing data from the National Health and Nutrition Examination Survey (NHANES) database (2009-2010), we selected 1294 and 1778 men aged ≥40 years from a pool of 10 537 participants, ensuring no missing information. Regression analyses examined the associations between leafy/lettuce salad intake, daily nutrient intake, and the odds of PCa. Results: Univariable MR (UVMR) analysis reveals that the intake of pork and salad/raw vegetable correlated with an elevated PCa risk. Subsequent to confounder adjustment via multivariable MR (MVMR) analysis, a causal link was established between salad/raw vegetable intake and an increased risk of PCa (odds ratio [OR]: 1.658, 95% confidence interval [95% CI]: 1.037-2.644, P = 0.046). The analysis based on NHANES datasets demonstrated a link between leafy/lettuce salad intake and heightened odds of PCa (OR: 1.025, 95% CI: 1.003-1.049, P = 0.038). Increased daily intakes of β-carotene (original OR: 1.00006, 95% CI: 1.00001-1.00011, P = 0.024) and vitamin B1 (OR: 1.474, 95% CI: 1.104-1.967, P = 0.014) were associated with a higher likelihood of PCa. Conclusions: These MR analyses substantiate the causal nexus between salad/raw vegetable intake and PCa risk. Similarly, leafy/lettuce salad intake and the odds of PCa were significantly correlated in the cross-sectional observational study. Moreover, higher daily intakes of β-carotene and vitamin B1 were linked to an increased likelihood of PCa. These findings provide practical dietary recommendations for PCa prevention and enhance early identification and diagnosis.

How might acne and prostate cancer be connected?

Acne and prostate cancer are in part indirectly connected by dietary characteristics that lead to overstimulation of cellular growth signaling. Further, they are directly connected by a proinflammatory phylotype of the acne related bacterium, Cutibacterium acnes, which spreads from acne affected skin to prostate tissue and exists there chronically within a biofilm it secretes, resulting in a local inflammatory and immunosuppressive microenvironment, eventually culminating in prostate cancer initiation and progression. The diet-acne-prostate cancer nexus needs to be explored further and has implications regarding diet, antibiotics, and vaccinations in the prevention and treatment of prostate cancer.

Abstract B106: Empowering communities: Prostate cancer short training pilot program

Abstract The prostate cancer short training was designed to empower cancer survivors, their families, and advocates by providing comprehensive insights into prostate cancer research, prevention, and practical advocacy strategies. Participants were equipped with effective communication methodologies to disseminate information to their close circles and broader networks, thereby establishing a reputable source of information within their communities. The primary aim was to develop and evaluate a bilingual program focused on educating and empowering individuals within Hispanic/Latino communities to advocate for prostate cancer awareness. Sessions were conducted in both English and Spanish, and materials were culturally tailored to the Hispanic/Latino demographic. The overarching objectives included educating on risk factors, screening techniques and reinforcing advocacy for prostate cancer awareness. This training aspired to cultivate an inclusive community of informed advocates, advancing cancer awareness, support systems, and treatment accessibility. The Prostate Cancer Short Training served as an exclusive standalone session structured to provide participants with comprehensive knowledge regarding prostate cancer. It was delivered by the Florida California CaRE2 Health Equity Center, a partnership comprising three universities, the Florida A&M University, the University of Florida, and the University of Southern California. The training addresses prostate cancer and its disproportionate impact among thee Hispanic/Latino population. Pre- and post-tests were applied to assess participants' knowledge, self-efficacy, and intent to disseminate prostate cancer information. We present data from the 2024 Prostate Cancer Training pilot cohort (pre, N=11, post, N=11). The 11 participants were all of Hispanic/Latino ethnicity with 81.8% female participants and 18.2% male respectively. Participants demonstrated a notable increase in knowledge, with a 72% difference in correct responses between pre and post-assessment. No decline was observed in post-test scores. Our statistical analysis on knowledge, yielded p-values of 0.013, 0.13, 0.041, 0.074, >0.9, 0.041, and >0.9. Furthermore, there was an increase in self-efficacy and intention to disseminate cancer information among participants. In conclusion, we present findings from a Prostate Cancer Short Training pilot program designed for Hispanic/Latino adults, aimed at fostering advocacy within this demographic. Additionally, we underscore the significance of short training initiatives within the community to further support the overarching mission of eliminating cancer health disparities, particularly concerning Hispanic/Latino men, within the program's context. Citation Format: Ileana Guzman, Nazleen Del Rio, Brooke Hensel, Carolina Aristizabal, Eduardo Ibarra, Rosa Barahona, Lourdes Baezconde-Garbanati, Mariana C. Stern, Sandra Suther, John Luque, Fern J. Webb. Empowering communities: Prostate cancer short training pilot program [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B106.

Abstract B034: Understanding how family dynamics influence discussions about prostate cancer: A PEN-3 model analysis of shared risk communication within African American families

Abstract Background: Race and family history are important risk-stratifying variables for prostate cancer prevention and control. Despite their elevated risks for developing and dying from the disease, African-Americans are less knowledgeable about their shared familial risk than the general population. African American family structures are quite diverse. However, the manner in which this diversity influences the flow of shared risk information is largely absent from the literature. This study uses the PEN-3 cultural model to investigate how family dynamics influence prostate cancer information sharing within African American families. Method: Twenty-three members of ten families with African-American men completed semi-structured interviews in 2018 - 2019. Using a non-probability sampling scheme, nuclear, blended, extended, single-parent and cohabiting families were recruited to participate. The interview guide was structured to elicit information about participant's (a) family descriptions/family dynamics, (b) health communication patterns, (c) motivations for sharing health information, (d) health communication approaches, (e) handling of withheld information, and (f) generational communication strategies. All audio-recorded interviews were conducted by three African- American investigators and transcribed verbatim by a professional transcriptionist. All verbatim transcripts were entered into MAXQDA qualitative software for analysis using the PEN-3 model dimensions. Results: Cultural Identity - Personal/Extended: Families were more supportive of sharing sensitive health information with kinship group members who are viewed as close than distant. Neighborhood: The church family was sometimes viewed as an extension of the immediate family, particularly in situations where family members are geographically dispersed. Relationships and Expectations - Perceptions: Indirect communication is acceptable for relaying general information with young people, but direct communication is preferred for older adults. Cultural Empowerment - Negative: Withholding information to protect other's emotions can sometimes result in feelings of exclusion or mistrust when those being protected discover that information was withheld. Conclusion/Discussion: These findings highlight the complexity of family dynamics in communicating shared prostate cancer risk information within African American families. The generational divide in communication preferences suggests that strategies are needed to bridge that gap. Citation Format: Levi Ross, Michael A. Preston, Linda Collins, Florida Uzoaru, Torhonda C. Lee. Understanding how family dynamics influence discussions about prostate cancer: A PEN-3 model analysis of shared risk communication within African American families [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B034.

Evaluation of circulating plasma proteins in prostate cancer using mendelian randomization

BackgroundThe proteome is an important resource for exploring potential diagnostic and therapeutic targets for cancer. This study aimed to investigate the causal associations between plasma proteins and prostate cancer (PCa), and to explore the downstream phenotypes that plasma proteins may influence and potential upstream intervening factors.MethodsProteome-wide Mendelian randomization was used to investigate the causal effects of plasma proteins on PCa. Colocalization analysis examined the common causal variants between plasma proteins and PCa. Summary-statistics-based Mendelian Randomization (SMR) analyses identified associations between the expression of protein-coding genes and PCa. Phenome-wide association study was performed to explore the effect of target proteins on downstream phenotypes. Finally, a systematic Mendelian randomization analysis between lifestyle factors and plasma proteins was performed to assess upstream intervening factors for plasma proteins.ResultsThe findings revealed a positive genetic association between the predicted plasma levels of nine proteins and an elevated risk of PCa, while four proteins exhibited an inverse association with PCa risk. SMR analyses revealed ZG16B, PEX14 in blood and ZG16B, NAPG in prostate tissue were potential drug targets for PCa. The genetic association of PEX14 with PCa was further supported by colocalization analysis. Further Phenome-wide association study showed possible side effects of ZG16B, PEX14 and NAPG as drug targets. 10 plasma proteins (RBP7, TPST1, NFASC, LAYN, HDGF, SERPIMA5, DLL4, EFNA3, LIMA1, and CCL27) could be modulated by lifestyle-related factors.ConclusionThis study explores the genetic associations between plasma proteins and PCa, provides evidence that plasma proteins serve as potential drug targets and enhances the understanding of the molecular etiology, prevention and treatment of PCa.

Role of Vitamins in Therapeutic and Targeting Approaches for Prostate Cancer: An Overview.

Vitamins play a crucial role in cellular functions like cell cycling and proliferation, differentiation, and apoptosis. These also help in the induction of cell cycle arrest and/or apoptosis. They can inhibit normal prostatic epithelial cell growth and might be helpful for the prevention of prostate cancer (PCa). Many essential vitamins including the fat-soluble vitamins (vitamin A, vitamin D, vitamin E, and vitamin K) and the water-soluble vitamins (vitamin B complexes and vitamin C) have a huge impact on the inhibition of growth and progression of PCa. Vitamins show anticancer properties and are involved in regulatory processes like the DNA repairing process, which inhibit the growth of PCa. Consumption of multivitamins prevents methylation of cancer cells and possesses an enormous potential that can be applied for the prevention as well as in the management of PCa. They have a great role in the inhibition of different signalling pathways involved in PCa. Moreover, they have also displayed a significant role in targeting of PCa with various nanocarrier systems. This review encompasses the recent studies about the individual actions of different vitamins and vitamin analogs, the combination of vitamins, and their efficient functions in various therapeutic and targeting approaches for PCa.

Epigenetics of Dietary Phytochemicals in Cancer Prevention: Fact or Fiction.

Cancer development takes 10 to 50 years, and epigenetics plays an important role. Recent evidence suggests that ~80% of human cancers are linked to environmental factors impinging upon genetics/epigenetics. Because advanced metastasized cancers are resistant to radiation/chemotherapeutic drugs, cancer prevention by relatively nontoxic "epigenetic modifiers" will be logical. Many dietary phytochemicals possess powerful antioxidant and anti-inflammatory properties that are hallmarks of cancer prevention. Dietary phytochemicals can regulate gene expression of the cellular genome via epigenetic mechanisms. In this review, we will summarize preclinical studies that demonstrate epigenetic mechanisms of dietary phytochemicals in skin, colorectal, and prostate cancer prevention. Key examples of the importance of epigenetic regulation in carcinogenesis include hypermethylation of the NRF2 promoter region in cancer cells, resulting in inhibition of NRF2-ARE signaling. Many dietary phytochemicals demethylate NRF2 promoter region and restore NRF2 signaling. Phytochemicals can also inhibit inflammatory responses via hypermethylation of inflammation-relevant genes to block gene expression. Altogether, dietary phytochemicals are excellent candidates for cancer prevention due to their low toxicity, potent antioxidant and anti-inflammatory properties, and powerful epigenetic effects in reversing procarcinogenic events.

PiRNA PROPER Suppresses DUSP1 Translation by Targeting N6-Methyladenosine-Mediated RNA Circularization to Promote Oncogenesis of Prostate Cancer.

Genetic and epigenetic alterations occur in many physiological and pathological processes. The existing knowledge regarding the association of PIWI-interacting RNAs (piRNAs) and their genetic variants on risk and progression of prostate cancer (PCa) is limited. In this study, three genome-wide association study datasets are combined, including 85,707 PCa cases and 166,247 controls, to uncover genetic variants in piRNAs. Functional investigations involved manipulating piRNA expression in cellular and mouse models to study its oncogenetic role in PCa. A specific genetic variant, rs17201241 is identified, associated with increased expression of PROPER (piRNA overexpressed in prostate cancer) in tumors and are located within the gene, conferring an increased risk and malignant progression of PCa. Mechanistically, PROPER coupled with YTHDF2 to recognize N6-methyladenosine (m6A) and facilitated RNA-binding protein interactions between EIF2S3 at 5'-untranslated region (UTR) and YTHDF2/YBX3 at 3'-UTR to promote DUSP1 circularization. This m6A-dependent mRNA-looping pattern enhanced DUSP1 degradation and inhibited DUSP1 translation, ultimately reducing DUSP1 expression and promoting PCa metastasis via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of PROPER expression using antagoPROPER effectively suppressed xenograft growth, suggesting its potential as a therapeutic target. Thus, targeting piRNA PROPER-mediated genetic and epigenetic fine control is a promising strategy for the concurrent prevention and treatment of PCa.

Upregulation of CKS2 in immunosuppressive cells is associated with metastasis and poor prognosis in prostate cancer: a single-cell RNA-sequencing analysis.

Metastasis worsens prostate cancer (PCa) prognosis, with the immunosuppressive microenvironment playing a key role in bone metastasis. This study aimed to investigate how an immunosuppressive environment promotes PCa metastasis and worsens prognosis of patients with PCa. Candidate oncogenes were identified through analysis of the Gene Expression Omnibus (GEO) database. A prognostic model was developed for the purpose of identifying target genes. A single-cell RNA sequencing data from GEO database was used to analyze the localization of target genes in the tumor microenvironment. A pan-cancer analysis was conducted to study the cancer-causing potential of target genes across different types of tumors. Fifty-one genes were found to be differentially expressed in bone metastasis compared to non-metastatic PCa, with CKS2 identified as the most significant gene associated with poor prognosis. CKS2 was shown to be linked to an immunosuppressive microenvironment and osteoclastic bone metastases, as shown by its negative correlation with immune cell infiltration and osteoblast-related gene expression. Moreover, CKS2 was found in immunosuppressive cells and was linked to bone metastasis in PCa. It was also overexpressed in different types of tumors, making it as an oncogenic gene. This research offers a new perspective on the potential utility of CKS2 as a therapeutic target for the prevention of metastatic PCa.

Effect of Selol on Tumor Morphology and Biochemical Parameters Associated with Oxidative Stress in a Prostate Tumor-Bearing Mice Model.

Prostate cancer is the leading cause of cancer death in men. Some studies suggest that selenium Se (+4) may help prevent prostate cancer. Certain forms of Se (+4), such as Selol, have shown anticancer activity with demonstrated pro-oxidative effects, which can lead to cellular damage and cell death, making them potential candidates for cancer therapy. Our recent study in healthy mice found that Selol changes the oxidative-antioxidative status in blood and tissue. However, there are no data on the effect of Selol in mice with tumors, considering that the tumor itself influences this balance. This research investigated the impact of Selol on tumor morphology and oxidative-antioxidative status in blood and tumors, which may be crucial for the formulation's effectiveness. Our study was conducted on healthy and tumor-bearing animal models, which were either administered Selol or not. We determined antioxidant enzyme activities (Se-GPx, GPx, GST, and TrxR) spectrophotometrically in blood and the tumor. Furthermore, we measured plasma prostate-specific antigen (PSA) levels, plasma and tumor malondialdehyde (MDA) concentration as a biomarker of oxidative stress, selenium (Se) concentrations and the tumor ORAC value. Additionally, we assessed the impact of Selol on tumor morphology and the expression of p53, BCL2, and Ki-67. The results indicate that treatment with Selol influences the morphology of tumor cells, indicating a potential role in inducing cell death through necrosis. Long-term supplementation with Selol increased antioxidant enzyme activity in healthy animals and triggered oxidative stress in cancer cells, activating their antioxidant defense mechanisms. This research pathway shows promise in understanding the anticancer effects of Selol. Selol appears to increase the breakdown of cancer cells more effectively in small tumors than in larger ones. In advanced tumors, it may accelerate tumor growth if used as monotherapy. Therefore, further studies are necessary to evaluate its efficacy either in combination therapy or for the prevention of recurrence.

Performance of large language models (LLMs) in providing prostate cancer information

PurposeThe diagnosis and management of prostate cancer (PCa), the second most common cancer in men worldwide, are highly complex. Hence, patients often seek knowledge through additional resources, including AI chatbots such as ChatGPT and Google Bard. This study aimed to evaluate the performance of LLMs in providing education on PCa.MethodsCommon patient questions about PCa were collected from reliable educational websites and evaluated for accuracy, comprehensiveness, readability, and stability by two independent board-certified urologists, with a third resolving discrepancy. Accuracy was measured on a 3-point scale, comprehensiveness was measured on a 5-point Likert scale, and readability was measured using the Flesch Reading Ease (FRE) score and Flesch–Kincaid FK Grade Level.ResultsA total of 52 questions on general knowledge, diagnosis, treatment, and prevention of PCa were provided to three LLMs. Although there was no significant difference in the overall accuracy of LLMs, ChatGPT-3.5 demonstrated superiority over the other LLMs in terms of general knowledge of PCa (p = 0.018). ChatGPT-4 achieved greater overall comprehensiveness than ChatGPT-3.5 and Bard (p = 0.028). For readability, Bard generated simpler sentences with the highest FRE score (54.7, p < 0.001) and lowest FK reading level (10.2, p < 0.001).ConclusionChatGPT-3.5, ChatGPT-4 and Bard generate accurate, comprehensive, and easily readable PCa material. These AI models might not replace healthcare professionals but can assist in patient education and guidance.

Expression and immune infiltration studies of IL-33-ST2-NF-κB signaling pathway in prostate cancer.

To analyze the expression of interleukin-33 (IL-33), growth-stimulated expression gene 2 (ST2), nuclear factor-kappaB (NF-κB) and immune cell infiltration in prostate cancer, this study aims to provide an experimental basis for the clinical prevention and treatment of prostate cancer. The expression of IL-33 in PCa tissues was analyzed using TCGA, TIMER and HPA databases. Using the UALCAN database, the systematic exploration of the relationship between IL-33 and various clinicopathological parameters was conducted. The correlation between IL-33 expression and immune cell infiltration was investigated using TIMER, CIBERSORT and GEPIA databases. To verify these analyses, 22 cases of normal prostate (NP), 76 cases of benign prostatic hyperplasia (BPH), and 100 cases of PCa were recruited. Immunohistochemical staining was performed to examine the expression of IL-33, ST2, NF-κB, and the infiltration of immune cells. Correlations between these factors were then determined. The expression of IL-33, ST2 and NF-κB was significantly lower in PCa tissues compared with NP (p < 0.05). IL-33 was not associated with age in PCa but showed associations with race, molecular characteristics, lymph node metastatic status, TP53 mutation and tumor grade. Furthermore, IL-33 was associated with immune cell infiltration. Positive correlations were observed between IL-33 and ST2 expressions, as well as between IL-33 and CD68+ macrophages in BPH and PCa. IL-33, ST2 and NF-κB are lowly expressed in PCa tissues, their expression decreases with the increasing malignancy of cancer. IL-33, ST2 and NF-κB are factors associated with PCa immune infiltration. IL-33 has an inhibitory effect on prostate cancer through the IL-33/ST2/NF-κB signalling pathway.

Association between Bisphenol A and Prostate-Specific Antigen (PSA) among U.S. Older Males: National Health and Nutrition Examination Survey (NHANES), 2003-2012.

There is growing evidence indicating that environmental endocrine disruptors may influence the development of prostate cancer. Despite this, the connection between BPA and PSA levels is still not fully understood and appears intricate. In this study, we aimed to assess the link between BPA exposure and PSA levels using data from the NHANES database. We conducted a weighted linear regression, logistic regression analysis, natural cubic spline (NCS), subgroup analysis, and interaction analysis on 2768 participants. Urinary BPA was considered the independent variable, while PSA was the dependent variable. In the study, the average age of the participants selected was 62.70 years (±12.93). Age was negatively correlated with BPA, while PSA and BMI were positively correlated with BPA concentration (all of the p-value < 0.05). In the fully adjusted model, the weighted linear and logistic regression results showed that BPA was positively correlated with PSA and prostate cancer. NCS analysis results show that BPA and PSA have a non-linear relationship. Sensitivity and subgroup analyses showed similar results. In addition, there were interactions between BPA and age, PIR, education, HbA1c, high-density lipoprotein, smoking status, and Diabetes. There was a positive correlation between urinary BPA and PSA in older American males, especially when the BPA concentration was higher than 4.46 ng/mL. In future practical applications of prostate cancer screening, it is crucial to focus on individuals aged 75 years and older, as well as those with a PIR between 0 and 1, non-Hispanic black, and other risk groups to provide reference values for the primary and secondary prevention of prostate cancer.

The effect of SGLT2 inhibition on prostate cancer: Mendelian randomization and observational analysis using electronic healthcare and cohort data

We evaluated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on prostate cancer by evidence triangulation. Using Mendelian randomization, we found that genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio= 0.56, 95% confidence interval [CI]= 0.38 to 0.82; 79,148 prostate cancer cases and 61,106 controls), advanced, and early-onset prostate cancer. Using electronic healthcare data (nSGLT2i= 24,155; nDPP4i= 24,155), we found that the use of SGLT2 inhibitors was associated with a 23% reduced risk of prostate cancer (hazard ratio= 0.77, 95% CI= 0.61 to 0.99) in men with diabetes. Using data from two prospective cohorts (n4C= 57,779; nUK_Biobank= 165,430), we found little evidence to support the association of HbA1c with prostate cancer, implying a non-glycemic effect of SGLT2 inhibition on prostate cancer. In summary, this study provides multiple layers of evidence to support the beneficial effect of SGLT2 inhibition on reducing prostate cancer risk. Future trials are warranted to investigate whether SGLT2 inhibitors can be recommended for prostate cancer prevention.

Association between inflammatory cytokines and prostate cancer

IntroductionWe conducted bidirectional two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between 91 inflammatory cytokines and prostate cancer (PCa).Material and methodsThe Inverse Variance Weighted (IVW) model served as the primary two-sample MR analysis method, utilized to estimate the causal effect of exposure on the outcome. The Weighted Median (WM) and MR Egger methods were additionally employed to complement the IVW model. Sensitivity analyses were performed using Cochran's Q test for both the IVW and MR Egger methods. To assess the presence of horizontal pleiotropy, the instrumental variables (IVs) were subjected to the MR-Egger intercept test.ResultsFollowing Bonferroni correction, the IVW analysis revealed positive correlations between PCa and the levels of C-C motif chemokine 20 (CCL20), C-C motif chemokine 23 (CCL23), fibroblast growth factor 19 (FGF19), fibroblast growth factor 23 (FGF23), and interleukin-6 (IL-6). Notably, IL-6 exhibited the strongest positive association effect (odds ratio [95% confidence interval]: 1.0076 [1.0014, 1.0139]), followed by CCL-20 (1.0067 [1.0004, 1.0129]) and FGF23 ([1.0002, 1.0119]). Reverse MR analysis indicated a negative causal relationship between PCa and interleukin-22 receptor subunit alpha-1 levels (IL22RA1) (0.4852 [0.2390, 0.9847]).ConclusionsThis study proposes that there exists a positive correlation between the levels of CCL20, CCL23, FGF19, FGF23, and IL-6 and the occurrence of PCa. Furthermore, we found evidence to support the causal relationship between decreased levels of IL22RA1 and the development of PCa. These findings unveil novel biomarkers and pathways that could potentially be targeted for the prevention and clinical treatment of PCa.

Development of a Multidisciplinary Care Pathway for Fracture Prevention in Men with Prostate Cancer at Initiation of Androgen Deprivation Therapy.

Fracture risk is increased in men with prostate cancer (PCa) receiving Androgen Deprivation Therapy (ADT). However, routine assessment of fracture risk is often not systematically applied. We aimed to establish a comprehensive care pathway for fracture prevention in men with PCa starting ADT. Therefore, a multidisciplinary working group designed and implemented a care pathway using the 'Knowledge to Action' framework, based on current Dutch guidelines for PCa, osteoporosis and fracture prevention, and an extensive literature review of other guidelines. The pathway was developed according to a five-step clinical approach including case finding, fracture risk assessment based on risk factors, bone mineral density test, vertebral fracture assessment, differential diagnosis, treatment, and annual follow-up. Our fracture prevention care pathway for patients with PCa at the time of ADT initiation was designed to promote a patient-centered, multidisciplinary approach to facilitate the implementation of early fracture prevention measures.

The Influence of β-Carotene and Its Liposomal Form on the Expression of EMT Markers and Androgen-Dependent Pathways in Different Prostate Cell Lines.

Prostate cancer (PCa) is the most common malignancy in men. Although the prognosis in the early stages is good, the treatment of advanced PCa remains a formidable challenge. Even after an initial response to hormone therapy or chemotherapy, recurrences are frequent and resistance to any systemic treatment is common. β-Carotene (BC), a plant-derived tetraterpene, is known for its antioxidant capacity and can modulate multiple cellular signaling pathways, potentially affecting androgen synthesis. We investigated the influence of BC (dissolved in EtOH/THF with a cell culture medium or encapsulated in liposomes (LP-BCs)) on the viability, migration potential, and connective tissue cleavage capabilities of several PCa cell lines (Du145, LNCaP, PC-3, and 22Rv1) and a healthy prostate model (RWPE cells). BC significantly reduced the proliferative capacity of all investigated cell lines at various concentrations (1.5-30 µM) and decreased cell migration. However, it significantly increased the expression of epidermal-mesenchymal transition (EMT) master proteins in all cancer cell lines and RWPE (p < 0.05) These effects were not observed with LP-BCs. This study suggests that LP-BCs, with their higher antiproliferative capabilities and pronounced inhibition of the EMT, may be a more effective form of possible PCa prevention or treatment than the free form. LPs may also modulate lipid metabolism in PCa cells.

Inhibitors of the transactivation domain of androgen receptor as a therapy for prostate cancer

The androgen receptor (AR) is a modular transcription factor which functions as a master regulator of gene expression. AR protein is composed of three functional domains; the ligand-binding domain (LBD); DNA-binding domain (DBD); and the intrinsically disordered N-terminal transactivation domain (TAD). AR is transactivated upon binding to the male sex hormone testosterone and other androgens. While the AR may tolerate loss of its LBD, the TAD contains activation function-1 (AF-1) that is essential for all AR transcriptional activity. AR is frequently over-expressed in most prostate cancer. Currently, androgen deprivation therapy (ADT) in the form of surgical or chemical castration remains the standard of care for patients with high risk localized disease, advanced and metastatic disease, and those patients that experience biochemical relapse following definitive primary treatment. Patients with recurrent disease that receive ADT will ultimately progress to lethal metastatic castration-resistant prostate cancer. In addition to ADT not providing a cure, it is associated with numerous adverse effects including cardiovascular disease, osteoporosis and sexual dysfunction. Recently there has been a renewed interest in investigating the possibility of using antiandrogens which competitively bind the AR-LBD without ADT for patients with hormone sensitive, non-metastatic prostate cancer. Here we describe a class of compounds termed AR transactivation domain inhibitors (ARTADI) and their mechanism of action. These compounds bind to the AR-TAD to inhibit AR transcriptional activity in the absence and presence of androgens. Thus these inhibitors may have utility in preventing prostate cancer growth in the non-castrate setting.

Decursin Inhibits Expression and Nuclear Localization of DNMT and HDAC, and Suppresses the Growth and Survival of Prostate Cancer Cells

Background: DNA methyltransferases (DNMT) and histone deacetylases (HDAC) inhibitors have utility in cancer therapeutics. However, they are associated with toxicity, which limits their efficacy against carcinomas. Previously, we reported that decursin has anticancer activity against prostate cancer (PCa). In this study, we investigated its epigenetic role in inhibiting the survival of PCa cells. Methods and Results: PCa cell viability was evaluated using MTT and trypan blue assays. The effect of decursin on global methylation and gene-specific methylation was assessed by dot blot assay and MS-PCR, respectively. Differential expression of DNMTs and HDACs was analyzed through semi-quantitative RT-PCR and western blotting. The activity of these enzymes was measured using commercial kits. The nuclear localization of DNMTs and HDAC3 was assessed via immunoblotting. Results: Decursin decreased cell viability and global methylation in PCa cells. It diminished the expression of DNMT1, DNMT3A, DNMT3B, and pan-DNMT activities. Decursin also reduced nuclear levels and increased cytosolic levels of DNMT1 and DNMT3A. Additionally, it inhibited the expression and activity of HDACs, leading to increased total acetylation and H3K9/14 acetylation of histone H3. A reduction in nuclear localization of HDAC3 was observed in decursin-treated PCa cells. Overall, decursin reduced DNMT and HDAC expression and enhanced the nuclear export of DNMT1, DNMT3A, and HDAC3, leading to decreased activities of these enzymes. Conclusion: This study demonstrates the potent anticancer effects of decursin in prostate cancer cells through modulation of epigenetic mechanisms. Decursin decreased both overall and nuclear levels of DNMTs and HDACs. This effect is likely due to decursin’s inhibitory action on these enzymes, as indicated by decreased global methylation and increased histone H3 acetylation. These findings suggest that decursin has multi-faceted epigenetic modulatory properties, making it a promising therapeutic agent for prostate cancer prevention.