Aggressive Prostate Cancer Research Articles

Proportion of Gleason Score ≥8 Prostate Cancer on Biopsy and Tumor Aggressiveness in Matched Cohorts of East Asian and Non-East Asian Men.

Historically, Asia had a lower prostate cancer (PCa) incidence and mortality compared with Western countries, but the gap is narrowing. Paradoxically, Asians have been reported to present with more advanced disease though more favorable outcomes. Despite PCa becoming an emerging health priority in East Asia, our knowledge remains limited. We compared the prevalence of high-grade PCa on biopsy and disease progression after radical prostatectomy (RP) in East Asian men from Asia and non-East Asian men from Western countries. This retrospective cohort study included men who underwent prostate biopsy and RP at academic centers in Shanghai, China, and Toronto, Canada (2014-2019). The expanded RP cohort included East Asian men from Singapore (n=282) and non-East Asians from Paris (n=192). Primary endpoints included the proportion of men with Gleason score (GS) ≥8 on biopsy and metastasis-free survival (MFS) after RP for GS ≥8. Multivariable logistic regression and Cox proportional hazard models were performed. Propensity score matching was used to reduce imbalances between cohorts. PCa was found on biopsy in 2,343 of 4,905 (48%) East Asians and 2,317 of 3,482 (67%) non-East Asians (P<.001). Prostate-specific antigen (PSA) levels at presentation and the proportion of men with GS ≥8 were higher in East Asians than non-East Asians (12.4 vs 6.6 ng/mL and 15.0% vs 8.8%, respectively; both P<.001). On multivariable analysis, there was no difference in the proportion of men with GS ≥8 between matched cohorts with PSA <20 ng/mL (n=3,572; odds ratio, 1.05 [95% CI, 0.77-1.43]; P=.76). No difference in MFS was found after RP between matched cohorts (hazard ratio, 0.97 [95% CI, 0.55-1.70]; P=.92). This contemporary study demonstrates that East Asian men are equally as likely to harbor aggressive PCa on biopsy as non-East Asian men at PSA levels observed in screening programs, with no difference in disease aggressiveness after RP. The assumption that unfavorable PCa at diagnosis is more common but less aggressive in East Asians should be revisited and viewed in the context of the expected increase in the PCa burden worldwide.

Estimation of Selected Metals in the Tissues of Prostate Carcinoma Patients

It Indicated that the Prostate cancer is common it affects nearly one-third of male over the age of 45. For two fundamental reasons, prostate cancer (PCa) is a serious health issue and a good prospect for tissue-scale, individualized modeling of cancer progression. In vivo validation might be allowed due to its compact size and the ability to measure serum PSA, a for prostate cancer blood biomarker can be diagnosed with support if certain markers identified by immunohistochemistry on tissue sections can aid in the diagnosis of adenocarcinoma that is primary in the prostate gland or metastatic. The biology of prostate cancer can be deeply understood by the gene identification and gene patterns expression. Using the Affymetrix Uranium95a, U95b, and Uranium95c chip sets (37,777 genes and expression sequence tags), Comprehensive gene expression is performed study on 152 hompsapien samples, which were from men of all ages and included cancer tissues, prostate tissues next to tumors, and prostate tissue of donor. In the prostate tissues, the majority of metals show a random distribution; nevertheless, patients show comparatively more unpredictability than controls. However, our findings indicate that the pattern of gene expression in cancer-related tissues is altered to such an extent that it resembles the effects of a cancer field. In contrast to controls, PCA and CA demonstrated how hazardous metals interfered with the critical metals' normal physiological and metabolic roles in the prostate tissues of both patient groups. In comparison to hyperthyroid patients and controls, hypothyroid patients' prostate tissues had greater mean levels of Fe, Ni, Cr, and Hg. Additionally; we discovered that by employing a unique model, Prostate cancer aggressiveness can be predicted by gene expression patterns.

Spatial transcriptomics reveals strong association between SFRP4 and extracellular matrix remodeling in prostate cancer

Prostate tumor heterogeneity is a major obstacle when studying the biological mechanisms of molecular markers. Increased gene expression levels of secreted frizzled-related protein 4 (SFRP4) is a biomarker in aggressive prostate cancer. To understand how SFRP4 relates to prostate cancer we performed comprehensive spatial and multiomics analysis of the same prostate cancer tissue samples. The experimental workflow included spatial transcriptomics, bulk transcriptomics, proteomics, DNA methylomics and tissue staining. SFRP4 mRNA was predominantly located in cancer stroma, produced by fibroblasts and smooth muscle cells, and co-expressed with extracellular matrix components. We also confirmed that higher SFRP4 gene expression is associated with cancer aggressiveness. Gene expression of SFRP4 was affected by gene promotor methylation. Surprisingly, the high mRNA levels did not reflect SFRP4 protein levels, which was much lower. This study contributes previously unknown insights of SFRP4 mRNA in the prostate tumor environment that potentially can improve diagnosis and treatment.

P018 Prostate cancer radiogenomics analysis reveals links between mpMRI and transcriptomics features in aggressive prostate cancer

P018 Prostate cancer radiogenomics analysis reveals links between mpMRI and transcriptomics features in aggressive prostate cancer

Role of Apparent Diffusion Coefficient Value and Apparent Diffusion Coefficient Ratio as Prognostic Factors for Prostate Cancer Aggressiveness.

Prostate cancer is one of the most prevalent cancers in the male population. To determine the aggressiveness of suspected lesions precisely, predictive models are increasingly being developed using quantitative MRI measurements, and particularly the ADC value. This study aimed to determine whether ADC values could be used to establish the aggressiveness of prostate cancer. A retrospective single-center study included 398 patients with prostate cancer who underwent a multiparametric MRI prior to radical prostatectomy. DWI ADC values were measured (µm2/s) using b values of 50 and 1000. The dominant lesion best visualized on MRI was analyzed. The ADC values of the index lesion and reference tissue were compared to tumor aggressivity according to the Gleason grade groups based on radical prostatectomy results. Statistical analysis was performed using the Mann-Whitney U test, Kruskal-Wallis H test, Spearman's rank correlation, and ROC curves. A very strong negative correlation (rs = -0.846, p < 0.001) between ADC and GS was found. ROC analysis revealed an AUC of 0.958 and an ADC threshold value of 758 µm2/s in clinically significant prostate cancer diagnoses using the absolute ADC value, with no advantage of using the ADC ratio over the absolute ADC value being identified. DWI ADC values and the calculated ADC ratio have a significant inverse correlation with GS. The findings indicate a strong capability in determining prostate cancer aggressiveness, as well as the possibility of assisting with assigning PI-RADS categories using ADC as quantitative metrics.

5hmC-profiles in Puerto Rican Hispanic/Latino men with aggressive prostate cancer.

Puerto Rican (PR) Hispanic/Latino (H/L) men are an understudied population that has the highest prostate cancer (PCa) specific mortality among other Hispanic populations. Little information is known about the higher mortality in PR H/L men. It is thought that epigenetic changes in key genes may play a critical role in aggressive tumors. We aimed to identify key 5-hydroxymethylcytosine (5hmC) changes in PR H/L men with aggressive PCa. We performed sequencing analysis using the 5hmC-enriched DNA from 22 prostate tumors and 24 adjacent normal FFPE samples. We identified 808 differentially methylated genes (DMGs) in tumors compared to adjacent normal tissues (FDR<0.05, log2FC>|0.4|). Pathway analysis of DMGs demonstrated that DNA repair pathway was most upregulated in tumors. Since 5hmC abundance positively correlates with gene expression levels, we further investigated 808 DMGs in TCGA PCa gene expression data. Further, we identified 59 DMGs (80.1%, FDR<0.05, ΔGE (gene expression) >|1|) with significant gene expression changes in the same direction. Additionally, we identified 111 aggressiveness-related DMGs, of which, two hypomethylated genes ( CCDC122 , NUDT15 ) and four hypermethylated genes ( PVT1 , RPL30 , TRMT12 , UBR5 ) were found to be altered at transcriptomic level in a concordant manner in PR H/L PCa patients (N=86). The aberrant 5hmC (N=55) and GE (N=497) changes in these six genes were also associated with progression-free survival in the mixed PCa population. In conclusion, our study identified 59 DMGs showing concordant epigenetic and transcriptomic changes in tumor tissues and 111 DMGs showing association with aggressive PCa among PR H/L men.

Correlation of magnetic resonance imaging and computed tomography with biological factor expression and lymph node metastasis in aggressive prostate cancer.

This paper focused on probing the correlation of magnetic resonance imaging (MRI) and computed tomography (CT) manifestations with biological factor expression and lymph node metastasis (LNM) in aggressive prostate cancer (PCa). A total of 136 PCa patients underwent surgical treatment, and received CT and MRI examinations before surgery, whereby the apparent diffusion coefficient (ADC) values of quantitative MRI (qMRI) parameters were obtained. Patients were categorized into the non-aggressive PCa group and aggressive PCa group according to the postoperative pathological results and Gleason scores. The expression of biological factors [prostate-specific antigen (PSA), proliferating cell nuclear antigen (PCNA), p27, and ki-67] in both groups was tested. CT and MRI manifestations of aggressive PCa patients were analyzed. The qMRI parameters, biological factors levels and LNM were compared in two groups; the relationships between CT and MRI manifestations, qMRI parameters and positive expression of biological factors and LNM were probed in two groups. In the aggressive PCa group, MRI and CT presented different degrees of abnormal prostate changes. In the aggressive PCa group, PSA and p27 expression and ADC values were lower, and PCNA and ki-67, and LNM rates were higher. Patients' LNM rate was higher than that of ≤ 2 cm when the tumor diameter was &gt; 2 cm. ADC values were positively correlated with PSA and p27 positive expression, and negatively correlated with PCNA, ki-67 and LNM in the aggressive PCa group. MRI and CT manifestations of aggressive PCa had certain characteristics; MRI manifestations and qMRI possessed a correlation with biological factors and LNM; ADC could be employed to assess the aggressiveness of PCa.

Germline DNA damage repair variants and prognosis of patients with high-risk or metastatic prostate cancer.

Deleterious germline variants in certain DNA repair genes are risk factors for developing aggressive prostate cancer. The objective was to quantify their prognostic impact after prostate cancer diagnosis. Men with prostate cancer, predominantly of European ancestry, were included from four cohorts with long-term follow-up. Pathogenic or likely pathogenic germline variants in 26 DNA repair genes were assessed in relation to metastasis-free survival in high-risk, localized prostate cancer and to overall survival in metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Among 3,525 patients initially diagnosed with non-metastatic prostate cancer, 2,594 had high-risk localized prostate cancer, 429 mCSPC, and 502 mCRPC at inclusion. BRCA2 variant carriers did not have worse metastasis-free survival in high-risk localized prostate cancer (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.69, 1.46) or overall survival in mCSPC (HR 0.46, 95% CI 0.14, 1.45) or mCRPC (HR 0.60, 95% CI 0.31, 1.17) compared to non-carriers of DNA repair variants. Among 868 additional patients with de novo metastatic (M1) prostate cancer, BRCA2 variant carriers tended to have worse overall survival (HR 1.59, 95% CI 1.01, 2.51). BRCA2 prognostic associations were not explained by radiation, PARP inhibitor, or platinum therapy. Results for other genes were limited in precision because variants were less common. Among patients with high-risk or metastatic prostate cancer who were initially diagnosed with and treated for non-metastatic tumors, germline DNA repair variants in BRCA2 do not confer a substantially worse prognosis.

Investigation of association between clinically significant prostate cancer, obesity and platelet to-lymphocyte ratio and neutrophil -to-lymphocyte ratio

IntroductionSeveral blood markers of inflammation are elevated in prostate cancer (PCa) and have prognostic value. Little is known about the relationship between these markers, PCa, and other factors associated with chronic inflammation, such as smoking and obesity. We analyzed the interaction between neutrophil and platelet counts indexed to lymphocyte count (NLR and PLR, resp.) and clinically significant PCa (csPCa), accounting for the potential confounding factors of systemic inflammation.MethodsNLR and PLR were evaluated in a multicenter prospective study in 443 patients. CsPCa was defined as a Gleason ≥ 4 + 3. Differences between patients with csPCa and non-csPCA were evaluated using the chi-square test, analysis of variance or the Kruskal-Wallis test. Multivariable logistic regression analysis adjusted for smoking, hypertension, diabetes, and cardiovascular disease, and in separate models, either body mass index or waist-to-hip ratio was used to characterize the relationship between inflammation and csPCa.ResultsNone of the factors such as plateletcrit, NLR, and PLR were significantly different between patients with csPCa or non-significant PCa. After adjustment, there was no association between PLR, NLR, plateletcrit or platelet count and csPCa. In an exploratory analysis, there was no association between markers of inflammation and PSA levels > 10 ng/mL. When testing different NLR cutoffs to predict csPCa in ROC analysis, none reached a clinically meaningful value.ConclusionIn contrast to previous studies, we found no significant association between easily available blood markers of inflammation and indices of PCa aggressiveness. Further research is required to determine whether inflammation promotes PCa. (ClinicalTrials.gov: NCT03127631. Date of registration: April 25, 2017.

To Drink or Not to Drink? Investigating Alcohol’s Impact on Prostate Cancer Risk

Background/Objectives: Prostate cancer (PCa) is a significant global health issue. The relationship between alcohol consumption and PCa risk has been the subject of extensive research, yet findings remain inconsistent. This review aims to clarify the association between alcohol intake and PCa risk, its aggressiveness, and the potential metabolic pathways involved in PCa onset. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed and MEDLINE, focusing on epidemiological studies, meta-analyses, cohort studies, and case–control studies. Studies evaluating alcohol consumption, prostate-specific antigen (PSA) levels, and PCa risk were included. The review also explored the roles of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in alcohol metabolism. Results: The analysis reveals a complex relationship between alcohol consumption and PCa. Heavy alcohol intake is associated with an increased risk of PCa, particularly more aggressive forms, and higher mortality rates. However, studies also show weak or no association between moderate alcohol consumption and PCa. The variability in findings may be attributed to differences in alcohol types, regional factors, and study methodologies. Conclusions: The link between alcohol consumption and PCa risk is multifaceted. While heavy drinking appears to increase the risk of aggressive PCa, the overall relationship remains unclear. Further research is needed to better understand these associations and inform public health recommendations and cancer prevention strategies.

Functional interaction between receptor tyrosine kinase MET and ETS transcription factors promotes prostate cancer progression.

Prostate cancer, the most common malignancy in men, has a relatively favourable prognosis. However, when it spreads to the bone, the survival rate drops dramatically. The development of bone metastases leaves patients with aggressive prostate cancer, the leading cause of death in men. Moreover, bone metastases are incurable and very painful. Hepatocyte growth factor receptor (MET) and fusion of genes encoding E26 transformation-specific (ETS) transcription factors are both involved in the progression of the disease. ETS gene fusions, in particular, have the ability to induce the migratory and invasive properties of prostate cancer cells, whereas MET receptor, through its signalling cascades, is able to activate transcription factor expression. MET signalling and ETS gene fusions are intimately linked to high-grade prostate cancer. However, the collaboration of these factors in prostate cancer progression has not yet been investigated. Here, we show, using cell models of advanced prostate cancer, that ETS translocation variant 1 (ETV1) and transcriptional regulator ERG (ERG) transcription factors (members of the ETS family) promote tumour properties, and that activation of MET signalling enhances these effects. By using a specific MET tyrosine kinase inhibitor in a humanised hepatocyte growth factor (HGF) mouse model, we also establish that MET activity is required for ETV1/ERG-mediated tumour growth. Finally, by performing a comparative transcriptomic analysis, we identify target genes that could play a relevant role in these cellular processes. Thus, our results demonstrate for the first time in prostate cancer models a functional interaction between ETS transcription factors (ETV1 and ERG) and MET signalling that confers more aggressive properties and highlight a molecular signature characteristic of this combined action.

Plant-based diets and urological health.

Plant-based diets have grown in popularity owing to multiple health and environmental benefits. Some evidence suggests that plant-based diets are associated with benefits for urological health. In genitourinary oncology, most research has focused on prostate cancer. Clinical trial results suggest a favourable influence of healthy lifestyle modifications including plant-based diets before and after prostate cancer treatment. Epidemiological evidence shows that a diet higher in plant-based and lower in animal-based food is associated with a lower risk of aggressive prostate cancer and better quality-of-life scores than a diet with less plant-based and more animal-based food. Studies on bladder and kidney cancer are scarce, but limited data suggest that vegetarian or plant-forward dietary patterns (increased consumption of fruits and vegetables and minimizing meat) are associated with a lower risk of development of these cancers than dietary patterns with fewer fruits and vegetables and more meat. With respect to benign urological conditions, epidemiological studies suggest that plant-based dietary patterns are associated with a lower risk of benign prostatic hyperplasia and urinary tract infections than non-plant-based dietary patterns. Compared with diets high in animal-based foods and low in plant-based foods, a substantial body of epidemiological evidence also suggests that increased consumption of healthy plant-based food is associated with a lower risk of erectile dysfunction. Plant-based dietary patterns that are high in fruits and vegetables with normal calcium intake, while limiting animal protein and salt, are associated with a lower risk of kidney stone development than dietary patterns that do not follow these parameters. Overall, increasing consumption of plant-based foods and reducing intake of animal-based foods has favourable associations with multiple urological conditions.

6667 IGF1 Induces The Expression of CYR61 In Metastatic Prostate Cancer

Abstract Disclosure: G.L. Ortiz Hernández: None. M. Walker: None. L. Woods-Burnham: None. R.A. Kittles: None. C.A. Casiano: None. S.L. Neuhausen: None. The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Our goal was to assess the contribution of the interaction of CYR61-IGF1 to PCa cell proliferation. Their combined role may explain a proportion of aggressive PCa. This study was designed to characterize the role of IGF1-induced expression of CYR61 in metastatic PCa cellular models and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, migration, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. In addition, we found that IGF1 induces protein expression of CYR61 in a time-dependent manner, validated by both immunoblotting and confocal microscopy. PC3 cell lines are androgen receptor negative (AR-) and glucocorticoid receptor positive (GR+), which is characteristic of aggressive, advanced metastatic castration-resistant prostate cancer (mCRPC). Currently, we are conducting the same experiments in LNCaP cells, which are AR+/GR-, to determine if the CYR61-IGF1 interplay also occurs in PCa cells capable of AR signaling. In conclusion, we found that CYR61 expression is induced by IGF1 and its inhibition decreased the capacity of metastatic PCa cells to proliferate. Our results suggest that CYR61 inhibition may have the potential for treating metastatic PCa. Presentation: 6/1/2024

6667 IGF1 Induces the Expression of CYR61 in Metastatic Prostate Cancer

Abstract Disclosure: G.L. Ortiz Hernández: None. M. Walker: None. L. Woods-Burnham: None. R.A. Kittles: None. C.A. Casiano: None. S.L. Neuhausen: None. The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Our goal was to assess the contribution of the interaction of CYR61-IGF1 to PCa cell proliferation. Their combined role may explain a proportion of aggressive PCa. This study was designed to characterize the role of IGF1-induced expression of CYR61 in metastatic PCa cellular models and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, migration, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. In addition, we found that IGF1 induces protein expression of CYR61 in a time-dependent manner, validated by both immunoblotting and confocal microscopy. PC3 cell lines are androgen receptor negative (AR-) and glucocorticoid receptor positive (GR+), which is characteristic of aggressive, advanced metastatic castration-resistant prostate cancer (mCRPC). Currently, we are conducting the same experiments in LNCaP cells, which are AR+/GR-, to determine if the CYR61-IGF1 interplay also occurs in PCa cells capable of AR signaling. In conclusion, we found that CYR61 expression is induced by IGF1 and its inhibition decreased the capacity of metastatic PCa cells to proliferate. Our results suggest that CYR61 inhibition may have the potential for treating metastatic PCa. Presentation: 6/1/2024

Stabilization of RRBP1 mRNA via an m6A-dependent manner in prostate cancer constitutes a therapeutic vulnerability amenable to small-peptide inhibition of METTL3

Mounting evidence has implicated the RNA m6A methylation catalyzed by METTL3 in a wide range of physiological and pathological processes, including tumorigenesis. The detailed m6A landscape and molecular mechanism of METTL3 in prostate cancer (PCa) remains ill-defined. We find that METTL3 is overexpressed in PCa and correlates with worse patient survival. Functional studies establish METTL3 as an oncoprotein dependent on its m6A enzymatic activity in both AR+ and AR− PCa cells. To dissect the regulatory network of m6A pathway in PCa, we map the m6A landscape in clinical tumor samples using m6A-seq and identify genome-wide METTL3-binding transcripts via RIP-seq. Mechanistically, we discover RRBP1 as a direct METTL3 target in which METTL3 stabilizes RRBP1 mRNA in an m6A-dependent manner. RRBP1 positively correlates with METTL3 expression in PCa cohorts and exerts an oncogenic role in aggressive PCa cells. Leveraging the 3D structural protein-protein interaction between METTL3 and METTL14, we successfully develop two potential METTL3 peptide inhibitors (RM3 and RSM3) that effectively suppress cancer cell proliferation in vitro and tumor growth in vivo. Collectively, our study reveals a novel METTL3/m6A/RRBP1 axis in enhancing aggressive traits of PCa, which can be therapeutically targeted by small-peptide METTL3 antagonists.

Compromised CDK12 activity causes dependency on the high activity of O-GlcNAc transferase.

O-GlcNAc transferase (OGT) coordinates with regulators of transcription, including cyclin-dependent kinase 12 (CDK12), the major transcription elongation kinase. Here, we use inhibitor- and knockdown-based strategies to show that co-targeting of OGT and CDK12 is toxic to prostate cancer cells. OGT catalyzes all nucleocytoplasmic O-GlcNAcylation and due to its essentiality in higher eukaryotes, it is not an ideal drug target. Our glycoproteomics-data revealed that short-term CDK12 inhibition induces hyper-O-GlcNAcylation of the spliceosome-machinery in different models of prostate cancer. By integrating our glycoproteomics-, gene essentiality- and clinical-data from CDK12 mutant prostate cancer patients, we identify the non-essential serine-arginine protein kinase 1 (SRPK1) as a synthetic lethal partner with CDK12-inactivation. Both normal and cancer cells become highly sensitive against inhibitors of OGT and SRPK1 if they have lowered activity of CDK12. Inactivating mutations in CDK12 are enriched in aggressive prostate cancer, and we propose that these patients would benefit from therapy targeting the spliceosome.

Overexpression of sialyl Lewisa carrying mucin-type glycoprotein in prostate cancer cell line contributes to aggressiveness and metastasis

Metastasis-promoting Lewis and sialyl Lewis antigens expressed on glycoproteins such as mucins are frequently displayed on the surface of prostate cancer cells and could thus be ideal candidates as measures of prostate cancer aggressiveness. The current study describes the altered expression of sialyl Lewisa (sLea) antigen attached to glycoproteins and key glycosyltransferases between normal prostate (RWPE-1) and cancerous cell lines (LNCaP and DU145). Our results suggest that the expression of sLea on different glycoproteins correlates with the aggressiveness of prostate cancer cells, as determined by flow cytometry and fluorescence microscopy. Blotting studies revealed that sLea-bearing glycoproteins, similar to mucins, are predominantly expressed in the more aggressive DU145 cells, followed by LNCaP cells. Immunohistochemistry technique showed a gradient of sLea expression, with low levels in low-grade prostate cancer (stage II/III) and increasing levels in high-grade cancer (stage IV), indicating its potential as a prognostic marker. Additionally, in qRT-PCR analysis significant upregulation of the glycosyltransferases GALNT5 and ST3GAL6 was observed, correlating with the increased sLea expression in LNCaP (3.2- and 14.5-fold) and DU145 (3.3- and 23.75-fold) cells. Our data indicates a correlation between sLea selectin ligand expression and prostate cancer aggressiveness. Furthermore, GALNT5 and ST3GAL6 could serve as benchmarks in PCa malignancy.

Periprostatic adipose tissue inhibits tumor progression by secreting apoptotic factors: A natural barrier induced by the immune response during the early stages of prostate cancer.

Prostate cancer (PCa) is the second most prevalent malignancy in men worldwide. The risk factors for PCa include obesity, age and family history. Increased visceral fat has been associated with high PCa risk, which has prompted previous researchers to investigate the influence of body composition and fat distribution on PCa prognosis. However, there is a lack of studies focusing on the mechanisms and interactions between periprostatic adipose tissue (PPAT) and PCa cells. The present study investigated the association between the composition of pelvic adipose tissue and PCa aggressiveness to understand the role played by this tissue in PCa progression. Moreover, PPAT-conditioned medium (CM) was prepared to assess the influence of the PPAT secretome on the pathophysiology of PCa. The present study included 50 patients with localized PCa who received robot-assisted radical prostatectomy. Medical records were collected, magnetic resonance imaging scans were analyzed and body compositions were calculated to identify the associations between adipose tissue volume and clinical PCa aggressiveness. In addition, CM was prepared from PPAT and perivesical adipose tissue (PVAT) collected from 25 patients during surgery, and its effects on the PCa cell lines C4-2 and LNCaP, and the prostate epithelial cell line PZ-HPV-7, were investigated using a cell proliferation assay and RNA sequencing (RNA-seq). The results revealed that the initial prostate-specific antigen level was significantly correlated with pelvic and periprostatic adipose tissue volumes. In addition, PPAT volume was significantly higher in patients with extracapsular tumor extension. PCa cell proliferation was significantly reduced when the cells were cultured in PPAT-CM compared with when they were cultured in control- and PVAT-CM. RNA-seq revealed that immune responses, and the cell death and apoptosis pathways were enriched in PPAT-CM-cultured cells indicating that the cytokines or other factors secreted from PPAT-CM induced PCa cell apoptosis. These findings revealed that the PPAT secretome may inhibit PCa cell proliferation by activating immune responses and promoting cancer cell apoptosis. This mechanism may act as a first-line defense during the early stages of PCa.

HMGA2 regulates GPX4 expression and ferroptosis in prostate cancer cells

Prostate cancer (PCa) remains a significant global health burden and an increase in oxidative stress is associated with cancer progression. High Mobility Group A2 (HMGA2), a chromatin architectural protein, increases oxidative stress and promotes sensitivity to ferroptosis inducers, however, the mechanism is unknown. We investigated the role of HMGA2 in GPX4 regulation and the impact on cellular responses to oxidative stress and ferroptosis sensitivity. We conducted UALCAN database analysis, western blot analysis, and lipid peroxidation assays to determine the relationship between HMGA2 and GPX4 and the levels of lipid reactive oxygen species in a panel of PCa cell lines, including an enzalutamide-resistant cancer cell line (C4–2B MDVR). Our results show an inverse relationship between HMGA2 and GPX4 expression with high HMGA2 and low GPX4 expression associated with higher Gleason score and lower survival probability in prostate adenocarcinoma (PRAD) patients, while low/moderate HMGA2 expression is positively associated with increased GPX4 expression and higher survival probability. Cell lines showed a moderately negative but not statistically significant correlation between HMGA2 and GPX4 expression, however, PC3 and DU145 PCa cells display higher lipid peroxides concomitant with higher endogenous levels of HMGA2 and low GPX4. Overexpression of wild-type HMGA2 in LNCaP and 22Rv1 cells leads to higher HMGA2 expression compared to Neo control and is associated with higher SLC7A11 and GPX4 expression, while interestingly truncated HMGA2 overexpression in LNCaP and 22Rv1 cells coincides with higher HMGA2 and reduced GPX4 expression, leading to increased lipid peroxides and susceptibility to ferroptosis. Overexpression of wild-type and truncated HMGA2 in 22Rv1 cells increases SLC7A11 mRNA yet differing GPX4 protein expression suggests posttranslational regulation of GPX4. Moreover, enzalutamide-resistant C4–2B MDVR cells display higher HMGA2 levels compared to C4–2B cells, as well as sensitivity to RSL3 ferroptosis inducer, which is partially reversed by ferroptosis inhibitor, ferrostatin-1. Interestingly, GPX4 expression is higher in C4–2B MDVR cells compared to C4–2B, and HMGA2 knockdown further increases its expression but does not significantly alter its susceptibility to ferroptosis. In conclusion, our study shows that HMGA2 regulation of GPX4 expression is complex and truncated HMGA2 downregulates GPX4 and increases lipid peroxides. Moreover, HMGA2-expressing cells including enzalutamide-resistant cells are susceptible to RSL-3-induced ferroptosis. Thus, ferroptosis sensitivity offers promising insights for the development of targeted therapeutic interventions for aggressive PCa.

Advanced electrochemical detection of pyrophosphatase activity in LNCaP cells utilizing in-situ redox of copper

The necessity for precise delineation and quantitation of pyrophosphatase (PPase) activities is underscored, especially in aggressive prostate cancer, driving the demand for more refined analytical techniques due to challenges associated with inadequate sensitivity and poor signal amplification. In response, a novel electrochemical method utilizing in-situ copper(II) (Cu(II))-based Fast Scan Cyclic Voltammetry (FSCV) is introduced for the advanced detection of PPase in LNCaP prostate cancer cells. This technique is characterized by the exploitation of competitive binding between Cu(II) and L-Phenylalanine (L-Phe) versus pyrophosphate (PPi), with FSCV technology enhanced by ohmic drop compensation to improve detection sensitivity and signal reliability. Through the application of the FSCV technique transitioned to Current(I)-Voltage(V) analysis, the signal generation is facilitated by an L-Phe-Cu(II) complex, driven by the redox reaction of in-situ Cu(II), specifically its rapid transition from the Cu(0) state back to the Cu(II) state. When this complex is anchored onto a gold substrate modified with cucurbit[7]uril (CB[7]) through supramolecular host–guest interactions, a significant FSCV signal is elicited. A detection limit of 0.05 mU/mL (S/N = 3) is subsequently achieved when the method is applied to the quantification of PPase concentration. Leveraging the FSCV method, we have effectively analyzed PPase activity in LNCaP cells, offering a fresh perspective on tumor marker analysis and fostering advancements in drug development.