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Prostate cancer (PCa), with high heterogeneity and poor prognosis, is one of the most common malignant tumors in men. Circular RNAs (circRNAs) have been identified in tumor progression and resistance to medication in numerous studies. However, the role of circ_0001047 in PCa is unclear. In this research, we found that circ_0001047 had low expression in PCa cells and tissues and was negatively correlated with testosterone secretion in vivo. Overexpression of circ_0001047 inhibited the proliferation, migration, invasion, and anti-apoptotic abilities of human PCa cells in vitro. Mechanistically, circ_0001047 promoted the expression of FKBP5 through sponge adsorption of miR-122-5p and then inhibited the proliferation, anti-apoptotic migration, and invasion abilities of PCa cells. In addition, overexpression of circ_0001047 enhanced the sensitivity of PCa cells to abiraterone by inhibiting AKT phosphorylation activation through upregulation of FKBP5/PHLPP1. This study revealed a novel mechanism by which circ_0001047 regulates PCa progression and treatment sensitivity via the miR-122-5p/FKBP5/PHLPP1/AKT axis. These findings deepen our comprehension of the molecular mechanisms in latent PCa progression and treatment resistance. [ABSTRACT FROM AUTHOR]

Copyright of Tijdschrift voor Urologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The cancer occurrence and progression are largely affected by the post-translational modifications (PTMs) of proteins. Currently, it has been shown that the relationship between ubiquitination and SUMOylation is highly complex and interactive. SUMOylation affects the process of ubiquitination and degradation of substrates. Contrarily, SUMOylation-related proteins are also regulated by the ubiquitination process thus altering their protein levels or activity. Emerging evidence suggests that the abnormal regulation between this crosstalk may lead to tumorigenesis. Purpose: In this review, we have discussed the study of the relationship between ubiquitination and SUMOylation, as well as the possibility of a corresponding application in tumor therapy. Methods: The relevant literatures from PubMed have been reviewed for this article. Conclusion: The interaction between ubiquitination and SUMOylation is crucial for the occurrence and development of cancer. A greater understanding of the crosstalk of SUMOylation and ubiquitination may be more conducive to the development of more selective and effective SUMOylation inhibitors, as well as a promotion of synergy with other tumor treatment strategies. [ABSTRACT FROM AUTHOR]

Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53 mutation / deletion co-occur in PCa patient specimens and this co-occurrence accelerates prostatic oncogenesis. p53 gain-of-function (GOF) mutants are now shown to bind to a unique DNA sequence in the CTNNB1 gene promoter and transactivate its expression. ERG and β-Catenin co-occupy sites at pyrimidine synthesis gene (PSG) loci and promote PSG expression, pyrimidine synthesis and PCa growth. β-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals β-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa. TP53 alteration and TMPRSS2-ERG fusion are often found together in prostate cancer. Here, the authors show that gain-of-function mutant p53 collaborates with ERG proto-oncogene to drive prostate cancer tumourigenesis by activating beta-catenin expression and afterwards pyrimidine synthesis. [ABSTRACT FROM AUTHOR]

Purpose: Our study was to determine whether immediate androgen deprivation therapy (ADT) plus radiotherapy (RT) extends survival in men with node-positive prostate cancer (PCa) after radical prostatectomy (RP) compared with those who received ADT alone. Methods: A total of 99 consecutive patients with pathological positive lymph nodes (pN1) PCa were included in this study to receive immediate ADT plus RT (n = 70) or to receive immediate ADT alone (n = 29). The primary endpoint was castration-resistant prostate cancer (CRPC) free survival; the secondary endpoints were distant metastasis-free survival. Cox regression was used to assess the independent risk factors for CRPC. Results: The median follow-up time was 34.0 (24.8, 47.8) months and 34.25 (23.0, 49.0) months, respectively, in the ADT + RT group and ADT-alone group. The 5-year CRPC-free survival rate was 79.5% and 58.3%, respectively, in the ADT + RT group and ADT-alone group (p = 0.308). The 5-year distant metastasis-free survival rate was 71.4% and 38.8, respectively, in the ADT + RT group and ADT-alone group (p = 0.478). Compared with ADT-alone group, we saw a modest, but no significant improvement in CRPC-free survival and distant metastasis-free survival in ADT + RT group. The results of Cox regression showed that positive lymph nodes ≥ 4 was an independent risk factor for CRPC (p = 0.041). Conclusions: We found that immediate ADT plus RT compared to ADT alone did not improve CRPC-free and metastasis-free survival. Multivariate Cox regression analyses also indicated that patients with positive lymph nodes < 4 may benefits from ADT plus RT. [ABSTRACT FROM AUTHOR]

Background: Human malignancies are composed of heterogeneous subpopulations of cancer cells with phenotypic and functional diversity. Among them, a unique subset of cancer stem cells (CSCs) has both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties. As such, CSCs are promising cellular targets for effective cancer therapy. At the molecular level, hyper-activation of multiple stemness regulatory signaling pathways and downstream transcription factors play critical roles in controlling CSCs establishment and maintenance. To regulate CSC properties, these stemness pathways are controlled by post-translational modifications including, but not limited to phosphorylation, acetylation, methylation, and ubiquitination. Conclusion: In this review, we focus on E3 ubiquitin ligases and their roles and mechanisms in regulating essential hallmarks of CSCs, such as self-renewal, invasion and metastasis, metabolic reprogramming, immune evasion, and therapeutic resistance. Moreover, we discuss emerging therapeutic approaches to eliminate CSCs through targeting E3 ubiquitin ligases by chemical inhibitors and proteolysis-targeting chimera (PROTACs) which are currently under development at the discovery, preclinical, and clinical stages. Several outstanding issues such as roles for E3 ubiquitin ligases in heterogeneity and phenotypical/functional evolution of CSCs remain to be studied under pathologically and clinically relevant conditions. With the rapid application of functional genomic and proteomic approaches at single cell, spatiotemporal, and even single molecule levels, we anticipate that more specific and precise functions of E3 ubiquitin ligases will be delineated in dictating CSC properties. Rational design and proper translation of these mechanistic understandings may lead to novel therapeutic modalities for cancer procession medicine. [ABSTRACT FROM AUTHOR]

Purpose: Prostate cancer is the second most common cancer diagnosed worldwide and the third most common cancer among men in India. This study's objective was to characterise the mutational landscape of Indian prostate cancer using whole-exome sequencing to identify population-specific polymorphisms. Methods: Whole-exome sequencing was performed of 58 treatment-naive primary prostate tumors of Indian origin. Multiple computational and statistical analyses were used to profile the known common mutations, other deleterious mutations, driver genes, prognostic biomarkers, and gene signatures unique to each clinical parameter. Cox analysis was performed to validate survival-associated genes. McNemar test identified genes significant to recurrence and receiver-operating characteristic (ROC) analysis was conducted to determine its accuracy. OncodriveCLUSTL algorithm was used to deduce driver genes. The druggable target identified was modeled with its known inhibitor using Autodock. Results: TP53 was the most commonly mutated gene in our cohort. Three novel deleterious variants unique to the Indian prostate cancer subtype were identified: POLQ, FTHL17, and OR8G1. COX regression analysis identified ACSM5, a mitochondrial gene responsible for survival. CYLC1 gene, which encodes for sperm head cytoskeletal protein, was identified as an unfavorable prognostic biomarker indicative of recurrence. The novel POLQ mutant, also identified as a driver gene, was evaluated as the druggable target in this study. POLQ, a DNA repair enzyme implicated in various cancer types, is overexpressed and is associated with a poor prognosis. The mutant POLQ was subjected to structural analysis and modeled with its known inhibitor novobiocin resulting in decreased binding efficiency necessitating the development of a better drug. Conclusion: In this pilot study, the molecular profiling using multiple computational and statistical analyses revealed distinct polymorphisms in the Indian prostate cancer cohort. The mutational signatures identified provide a valuable resource for prognostic stratification and targeted treatment strategies for Indian prostate cancer patients. The DNA repair enzyme, POLQ, was identified as the druggable target in this study. [ABSTRACT FROM AUTHOR]

Despite their contributions to the financial efficiency and environmental sustainability of industrial processes, robotic assembly and disassembly have been understudied in the existing literature. This is in contradiction to their importance in realizing the Fourth Industrial Revolution. More specifically, although most of the literature has extensively discussed how to optimally assemble or disassemble given products, the role of other factors has been overlooked. For example, and among other factors, the choices of the robots involved in implementing the sequence plans, which should ideally be taken into account throughout the whole chain consisting of design, assembly, disassembly, and reassembly, may greatly affect the underlying implications with a considerable impact on the viability and effectiveness of the measures aimed at substantiating, realizing, and strengthening the backbones of a circular economy. Isolating the foregoing operations from the rest of the components of the relevant ecosystems may lead to erroneous inferences toward both the necessity and efficiency of the underlying procedures. In this paper, we try to alleviate these shortcomings by comprehensively investigating the state of the art in robotic assembly and disassembly. We consider and review various aspects of manufacturing and remanufacturing frameworks while particularly focusing on their desirability for supporting a circular economy. [ABSTRACT FROM AUTHOR]

Purpose: Prostate cancer (PCa) lacks specific markers capable of distinguishing aggressive tumors from those with indolent behavior. Therefore, the aim of this study was to evaluate the immunostaining of candidate proteins (PTEN, AKT, TRPM8, and NKX3.1) through the immunohistochemistry technique (IHC) on patients with metastatic and non-metastatic PCa. Methods: Tissues from 60 patients were divided into three groups categorized according to prognostic parameters: better prognosis (n = 20), worse prognosis (n = 23), and metastatic (n = 17). Immunostaining was analyzed by a pathologist and staining classifications were considered according to signal intensity: (0) no staining, (+) weak, and (++ and +++) intermediate to strong. Results: AKT protein was associated (p = 0.012) and correlated (p = 0.014; Tau = − 0.288) with the prognostic groups. The immunostaining for TRPM8 (p = 0.010) and NKX3.1 (p = 0.003) proteins differed between malignant tumor and non-tumoral adjacent tissue as well as for proteins in cellular locations (nucleus and cytoplasm). TRPM8 was independently associated with the ISUP grade ≥ 4 (p = 0.024; OR = 8.373; 95% CI = 1.319–53.164). The NKX3.1 showed positive and predominantly strong immunostaining in all patients in both tumoral and non-tumoral adjacent tissues. All metastatic samples had positive immunostaining, with strong intensity for NKX3.1 (p = 0.021; Tau = − 0.302). In the non-metastatic group, this strong protein staining was not observed in any patients. Conclusion: This study confirmed that NKX3.1 is highly specific for prostate tissue and indicated that NKX3.1, AKT, and TRPM8 may be candidate markers for prostate cancer prognosis. [ABSTRACT FROM AUTHOR]

Previous evidences have demonstrated that anti-tumor effect of high-dose ascorbic acid is associated with the generation of reactive oxygen species (ROS) via autoxidation. Hypoxia induces therapy resistance in castration-resistant prostate cancer. As a mitochondrial respiration inhibitor, metformin has the potential to improve tumor oxygenation. In this study, we evaluate the anti-tumor effect of ascorbic acid combined with metformin in prostate cancer. We demonstrated that ascorbic acid inhibits prostate cancer cells proliferation by generating ROS, and metformin enhances the anti-tumor effects of ascorbic acid. Mechanistically, metformin reduces oxygen consumption rate and NADP+/NADPH value in prostate cancer cells, thereby increases the ROS content induced by ascorbic acid. In addition, our data demonstrated that ascorbic acid inhibits p-AKT signaling in a ROS-dependent pathway, leading to inhibition of p-mTOR expression. And metformin inhibits the p-mTOR expression by activating the AMPK signaling pathway, exerting a synergistic effect on tumor suppression with ascorbic acid. Furthermore, metformin improves tumor oxygenation, and the combined treatment effect of ascorbic acid and metformin were demonstrated in a xenograft model of prostate cancer. Taken together, our data demonstrate that metformin enhances the anti-tumor proliferation effect of ascorbic acid by increasing ROS content in castration-resistant prostate cancer. This provides a new strategy for the clinical application of high-dose ascorbic acid as an anti-tumor drug. Key messages: Ascorbic acid inhibits tumor growth by inducing ROS generation. As a mitochondrial respiration inhibitor, metformin inhibits cellular oxygen consumption rate to improve oxygenation of prostate cancer. Metformin enhances anti-tumor effect of ascorbic acid by increasing ROS content. Ascorbic acid inhibits the mTOR expression via PI3K-AKT pathway, and metformin inhibits the mTOR expression by inhibiting AMPK signaling in prostate cancer cells. [ABSTRACT FROM AUTHOR]

Combining immune checkpoint therapy (ICT) and targeted therapy holds great promises for broad and long-lasting anti-cancer therapies. However, combining ICT with anti-PI3K inhibitors have been challenging because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we find that intermittent but not daily dosing of a PI3Kα/β/δ inhibitor, BAY1082439, on Pten-null prostate cancer models could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNα/IFNγ pathway activation, β2-microglubin expression and CXCL10/CCL5 secretion. With its preferential regulatory T cell inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells, most likely via tertiary lymphoid structures. Once primed, tumors remain T cell-inflamed, become responsive to anti-PD-1 therapy and have durable therapeutic effect. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn "cold" tumors into T cell-inflamed ones, paving the way for successful ICT. Limited response to immune checkpoint inhibitors has been reported in patients with castration-resistant prostate cancer. Here the authors show that intermittent, but not continuous, treatment with an anti-PI3Kα/β/δ-inhibitor promotes anti-tumor immunity and response to PD-1 blockade in a preclinical Pten-null model of prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is the leading cause of cancer in men, and its incidence increases with age. Among other risk factors, pre-existing metabolic diseases have been recently linked with prostate cancer, and our current knowledge recognizes prostate cancer as a condition with important metabolic anomalies as well. In malignancies, metabolic disorders are commonly associated with aberrations in mTOR, which is the master regulator of protein synthesis and energetic homeostasis. Although there are reports demonstrating the high dependency of prostate cancer cells for lipid derivatives and even for carbohydrates, the understanding regarding amino acids, and the relationship with the mTOR pathway ultimately resulting in metabolic aberrations, is still scarce. Conclusions and perspectives: In this review, we briefly provide evidence supporting prostate cancer as a metabolic disease, and discuss what is known about mTOR signaling and prostate cancer. Next, we emphasized on the amino acids glutamine, leucine, serine, glycine, sarcosine, proline and arginine, commonly related to prostate cancer, to explore the alterations in their regulatory pathways and to link them with the associated metabolic reprogramming events seen in prostate cancer. Finally, we display potential therapeutic strategies for targeting mTOR and the referred amino acids, as experimental approaches to selectively attack prostate cancer cells. [ABSTRACT FROM AUTHOR]

Copyright of Tijdschrift voor Urologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: The molecular heterogeneity of prostate cancer (PCa) gives rise to distinct tumor subclasses based on epigenetic modification and gene expression signatures. Identification of clinically actionable molecular subtypes of PCa is key to improving patient outcome, and the balance between specific pathways may influence PCa outcome. It is also urgent to identify progression-related markers through cytosine-guanine (CpG) methylation in predicting metastasis for patients with PCa. Methods: We performed bioinformatics analysis of transcriptomic, and clinical data in an integrated cohort of 551 prostate samples. The datasets included retrospective The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. Two algorithms, Least Absolute Shrinkage and Selector Operation and Support Vector Machine-Recursive Feature Elimination, were used to select significant CpGs. Results: We found that PCa progression is more likely to occur after the third year through conditional survival (CS) analysis, and prostate-specific antigen (PSA) was a better predictor of Progression-free survival (PFS) than Gleason score (GS). Our study first demonstrated that PCa tumors have distinct expression profiles based on the expression of genes involved in androgen receptor (AR) and PI3K-AKT, which influence disease outcome. Our results also indicated that there are multiple phenotypes relevant to the AR-PI3K axis in PCa, where tumors with mixed phenotype may be more aggressive or have worse outcome than quiescent phenotype. In terms of epigenetics, we obtained CpG sites and their corresponding genes which have a good predictive value of PFS. However, various evidences showed that the predictive value of CpGs corresponding genes was much lower than GpG sites in Overall survival (OS) and PFS. Conclusions: PCa classification specific to AR and PI3K pathways provides novel biological insight into previously established PCa subtypes and may help develop personalized therapies. Our results support the potential clinical utility of DNA methylation signatures to distinguish tumor metastasis and to predict prognosis and outcomes. [ABSTRACT FROM AUTHOR]

Background: PABC, commonly defined as breast cancer diagnosed during or ≤ 1 year after pregnancy, accounts for 7% of all breast cancers in women ≤ 45 years. Compared to age-matched non-PABC patients, PABC is characterized by a particularly aggressive histopathologic profile with poorly differentiated and estrogen- and progesterone receptor negative tumors and associated high mortality rates. This study assessed the genomic background of triple-negative PABC tumors by detection of copy number alterations (CNAs). Methods: MLPA was used to compare CNAs in breast cancer-associated chromosomal loci between triple-negative PABC- and subtype-matched non-PABC patients. Both CNA patterns were evaluated by cluster analysis; associations between individual gene CNAs, pathological characteristics and survival were explored. Results: Triple-negative PABC tumors exhibited unique CNAs compared to non-PABC tumors, including enrichment for TOP2A copy number loss, an independent predictor of worse overall survival (HR 8.96, p = 0.020). Cluster analysis based on CNA profiles identified a triple-negative PABC-subgroup with a particularly poor prognosis, characterized by chromosome 8p copy number loss. Individual gene CNAs analysis revealed that FGFR1 copy number loss on chromosome 8p11.23 was an independent predictor of poor outcome in multivariate analysis (HR 3.59, p = 0.053) and predicted the development of distant metastases (p = 0.048). Conclusion: This study provides novel insights into the biology of triple-negative PABC tumors suggesting that CNAs, particularly 8p loss and TOP2A loss, are involved in the development of breast cancer during pregnancy. FGFR1 loss and TOP2A loss seem to be promising new biomarkers that independently identify subgroups of PABC patients with poor prognosis. These genomic biomarkers may provide clues for personalized therapy. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a malignant epithelial tumor of the prostate gland with a high male cancer incidence. Numerous studies indicate that abnormal function of ubiquitin–proteasome system (UPS) is associated with the progression and metastasis of PCa. E3 ubiquitin ligases, key components of UPS, determine the specificity of substrates, and substantial advances of E3 ubiquitin ligases have been reached recently. Herein, we introduce the structures and functions of E3 ubiquitin ligases and summarize the mechanisms of E3 ubiquitin ligases-related PCa signaling pathways. In addition, some progresses in the development of inhibitors targeting E3 ubiquitin ligases are also included. [ABSTRACT FROM AUTHOR]

Castration resistance is a lethal form of treatment failure of prostate cancer (PCa) and is associated with ligand-independent activation of the androgen receptor (AR). It is only partially understood how the AR mediates survival and castration-resistant growth of PCa upon androgen deprivation. We investigated integrative genomics using a patient-derived xenograft model recapitulating acquired, AR-dependent castration-resistant PCa (CRPC). Sequencing of chromatin immunoprecipitation using an anti-AR antibody (AR-ChIP seq) revealed distinct profiles of AR binding site (ARBS) in androgen-dependent and castration-resistant xenograft tumors compared with those previously reported based on human PCa cells or tumor tissues. An integrative genetic analysis identified several AR-target genes associated with CRPC progression including OPRK1, which harbors ARBS and was upregulated upon androgen deprivation. Loss of function of OPRK1 retarded the acquisition of castration resistance and inhibited castration-resistant growth of PCa both in vitro and in vivo. Immunohistochemical analysis showed that expression of OPRK1, a G protein-coupled receptor, was upregulated in human prostate cancer tissues after preoperative androgen derivation or CRPC progression. These data suggest that OPRK1 is involved in post-castration survival and cellular adaptation process toward castration-resistant progression of PCa, accelerating the clinical implementation of ORPK1-targeting therapy in the management of this lethal disease. Through comparative genomics using PDX models of androgen-dependent (AD) and androgen-resistant (AR) tumors, Makino et al. identify opioid receptor kappa 1 (OPRK1) as being associated with castration-resistance. Loss of OPRK1 function delays castration-resistance and inhibits castration-resistant growth of prostate cancer cells in culture and in vivo, suggesting OPRK1 as a therapeutic target. [ABSTRACT FROM AUTHOR]

Castration resistance is a lethal form of treatment failure of prostate cancer (PCa) and is associated with ligand-independent activation of the androgen receptor (AR). It is only partially understood how the AR mediates survival and castration-resistant growth of PCa upon androgen deprivation. We investigated integrative genomics using a patient-derived xenograft model recapitulating acquired, AR-dependent castration-resistant PCa (CRPC). Sequencing of chromatin immunoprecipitation using an anti-AR antibody (AR-ChIP seq) revealed distinct profiles of AR binding site (ARBS) in androgen-dependent and castration-resistant xenograft tumors compared with those previously reported based on human PCa cells or tumor tissues. An integrative genetic analysis identified several AR-target genes associated with CRPC progression including OPRK1, which harbors ARBS and was upregulated upon androgen deprivation. Loss of function of OPRK1 retarded the acquisition of castration resistance and inhibited castration-resistant growth of PCa both in vitro and in vivo. Immunohistochemical analysis showed that expression of OPRK1, a G protein-coupled receptor, was upregulated in human prostate cancer tissues after preoperative androgen derivation or CRPC progression. These data suggest that OPRK1 is involved in post-castration survival and cellular adaptation process toward castration-resistant progression of PCa, accelerating the clinical implementation of ORPK1-targeting therapy in the management of this lethal disease. Through comparative genomics using PDX models of androgen-dependent (AD) and androgen-resistant (AR) tumors, Makino et al. identify opioid receptor kappa 1 (OPRK1) as being associated with castration-resistance. Loss of OPRK1 function delays castration-resistance and inhibits castration-resistant growth of prostate cancer cells in culture and in vivo, suggesting OPRK1 as a therapeutic target. [ABSTRACT FROM AUTHOR]

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have direct clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer. Androgen receptor can promote tumour progression in desmoplastic small round cell tumour (DSRCT), an aggressive paediatric malignancy that predominantly affects young males. Here, the authors show that DSRCT is an AR-driven malignancy and sensitive to androgen deprivation therapy [ABSTRACT FROM AUTHOR]

The proprotein convertase PACE4 has demonstrated value as a viable therapeutic target in prostate cancer (PCa). A novel isoform named PACE4-altCT, which arises in neoplastic lesions, plays an important role in tumor progression and has been validated as a pharmacological target. With the discovery of its overexpression in PCa and the alternative splicing of its pre-RNA to generate an oncogenic C-terminally modified isoform named PACE4-altCT, understanding and validating its value as a potential biomarker is of great interest either from prognostic or targeted therapy intervention. Expression of ERG in LNCaP cells was used to investigate the relationship between ERG expression occurring in PCa cells and PACE4-altCT expression by Western blot and qPCR. Using immunohistochemistry, the expression levels of PACE4 isoforms in patient tissues were investigated and correlated with ERG tumor status and Gleason score. An ELISA method was developed using affinity purified recombinant protein and used for quantitative analysis of plasma concentrations of PACE4-altCT and used for correlation. In contrast with the consensual isoform, PACE4-altCT was only strongly overexpressed in prostate cancer patients, correlated with ERG expression levels. Despite its intracellular retention PACE4-altCT could be detected in the plasma of most patients with prostate cancer, whereas it was only found at low levels in normal patients whereas total plasmatic PACE4 levels did not vary significantly between groups. Our study demonstrates that PACE4-altCT is strongly overexpressed in prostate cancer using both immunohistochemical and ELISA techniques and may have some interesting potential as a biomarker. [ABSTRACT FROM AUTHOR]

Castration resistance is a lethal form of treatment failure of prostate cancer (PCa) and is associated with ligand-independent activation of the androgen receptor (AR). It is only partially understood how the AR mediates survival and castration-resistant growth of PCa upon androgen deprivation. We investigated integrative genomics using a patient-derived xenograft model recapitulating acquired, AR-dependent castration-resistant PCa (CRPC). Sequencing of chromatin immunoprecipitation using an anti-AR antibody (AR-ChIP seq) revealed distinct profiles of AR binding site (ARBS) in androgen-dependent and castration-resistant xenograft tumors compared with those previously reported based on human PCa cells or tumor tissues. An integrative genetic analysis identified several AR-target genes associated with CRPC progression including OPRK1, which harbors ARBS and was upregulated upon androgen deprivation. Loss of function of OPRK1 retarded the acquisition of castration resistance and inhibited castration-resistant growth of PCa both in vitro and in vivo. Immunohistochemical analysis showed that expression of OPRK1, a G protein-coupled receptor, was upregulated in human prostate cancer tissues after preoperative androgen derivation or CRPC progression. These data suggest that OPRK1 is involved in post-castration survival and cellular adaptation process toward castration-resistant progression of PCa, accelerating the clinical implementation of ORPK1-targeting therapy in the management of this lethal disease. Through comparative genomics using PDX models of androgen-dependent (AD) and androgen-resistant (AR) tumors, Makino et al. identify opioid receptor kappa 1 (OPRK1) as being associated with castration-resistance. Loss of OPRK1 function delays castration-resistance and inhibits castration-resistant growth of prostate cancer cells in culture and in vivo, suggesting OPRK1 as a therapeutic target. [ABSTRACT FROM AUTHOR]

Combining immune checkpoint therapy (ICT) and targeted therapy holds great promises for broad and long-lasting anti-cancer therapies. However, combining ICT with anti-PI3K inhibitors have been challenging because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we find that intermittent but not daily dosing of a PI3Kα/β/δ inhibitor, BAY1082439, on Pten-null prostate cancer models could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNα/IFNγ pathway activation, β2-microglubin expression and CXCL10/CCL5 secretion. With its preferential regulatory T cell inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells, most likely via tertiary lymphoid structures. Once primed, tumors remain T cell-inflamed, become responsive to anti-PD-1 therapy and have durable therapeutic effect. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn "cold" tumors into T cell-inflamed ones, paving the way for successful ICT. Limited response to immune checkpoint inhibitors has been reported in patients with castration-resistant prostate cancer. Here the authors show that intermittent, but not continuous, treatment with an anti-PI3Kα/β/δ-inhibitor promotes anti-tumor immunity and response to PD-1 blockade in a preclinical Pten-null model of prostate cancer. [ABSTRACT FROM AUTHOR]

Supraphysiologic androgen (SPA) inhibits cell proliferation in prostate cancer (PCa) cells by transcriptional repression of DNA replication and cell-cycle genes. In this study, quantitative glycoprotein profiling identified androgen-regulated glycoprotein networks associated with SPA-mediated inhibition of PCa cell proliferation, and androgen-regulated glycoproteins in clinical prostate tissues. SPA-regulated glycoprotein networks were enriched for translation factors and ribosomal proteins, proteins that are known to be O-GlcNAcylated in response to various cellular stresses. Thus, androgen-regulated glycoproteins are likely to be targeted for O-GlcNAcylation. Comparative analysis of glycosylated proteins in PCa cells and clinical prostate tissue identified androgen-regulated glycoproteins that are differentially expressed prostate tissues at various stages of cancer. Notably, the enzyme ectonucleoside triphosphate diphosphohydrolase 5 was found to be an androgen-regulated glycoprotein in PCa cells, with higher expression in cancerous versus non-cancerous prostate tissue. Our glycoproteomics study provides an experimental framework for characterizing androgen-regulated proteins and glycoprotein networks, toward better understanding how this subproteome leads to physiologic and supraphysiologic proliferation responses in PCa cells, and their potential use as druggable biomarkers of dysregulated AR-dependent signaling in PCa cells. [ABSTRACT FROM AUTHOR]

Abnormal expression of insulin gene enhancer-binding protein 1 (ISL1) has been demonstrated to be closely associated with cancer development and progression in several cancers. However, little is known about ISL1 expression in metastatic castration-resistant prostate cancer (CRPC). ISL1 has also been recognized as a positive modulator of epithelial–mesenchymal transition (EMT). In this study, we focused on ISL1 which showed maximum upregulation at the mRNA level in the enzalutamide-resistant cell line. Accordingly, we found that ISL1 was overexpressed in enzalutamide-resistant C4-2B cells and its expression was significantly related to EMT. Our findings reveal the important role of ISL1 in androgen receptor (AR)-dependent prostate cancer cell growth; ISL1 knockdown reduced the AR activity and cell growth. ISL1 knockdown using small-interfering RNA inhibited AR, PSA, and EMT-related protein expression in C4-2B ENZR cells. In addition, knock-down ISL1 reduced the levels of AKT and p65 phosphorylation in C4-2B ENZR cells and these suggest that knock-down ISL1 suppresses EMT in part by targeting the AKT/NF-κB pathway. Further, ISL1 downregulation could effectively inhibit tumor growth in a human CRPC xenograft model. Together, the present study shows that downregulation of ISL1 expression is necessary for overcoming enzalutamide resistance and improving the survival of CRPC patients. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that PTEN loss is associated with p110β signaling dependency, leading to the clinical development of p110β-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner. Understanding the mechanisms driving PI3K isoform dependency in prostate cancer can help the design of future clinical trials. Here, the authors show that gain-of-function mutations in PIK3CA or PIK3CB can confer PI3K p110 isoform dependency and that the direct inhibition of AKT may be superior to PI3K inhibition in PTEN-deficient prostate cancers. [ABSTRACT FROM AUTHOR]

The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 methylation modifies intra-domain interactions, favors DNA binding and enhances ERG transcriptional activity. In a genetically engineered mouse model of ERG fusion-positive prostate cancer (Pb-Cre4 Ptenflox/floxRosa26-ERG, ERG/PTEN), ERG K362 methylation is associated with PTEN loss and progression to invasive adenocarcinomas. In both ERG positive VCaP cells and ERG/PTEN mice, PTEN loss results in AKT activation and EZH2 phosphorylation at serine 21 that favors ERG methylation. We find that ERG and EZH2 interact and co-occupy several sites in the genome forming trans-activating complexes. Consistently, ERG/EZH2 co-regulated target genes are deregulated preferentially in tumors with concomitant ERG gain and PTEN loss and in castration-resistant prostate cancers. Collectively, these findings identify ERG methylation as a post-translational modification sustaining disease progression in ERG-positive prostate cancers. Although the TMPRSS2-ERG gene fusion is the most common alteration in human prostate cancer, its involvement in disease progression remains unclear. Here, the authors demonstrate that ERG is methylated by Enhancer of zest homolog 2 leading to enhanced transcriptional and oncogenic activity. [ABSTRACT FROM AUTHOR]

Resistance to drugs targeting the androgen receptor (AR) signaling axis remains an important challenge in the treatment of prostate cancer patients. Activation of alternative growth pathways is one mechanism used by cancer cells to proliferate despite treatment, conferring drug resistance. Through a kinome-centered CRISPR-Cas9 screen in CWR-R1 prostate cancer cells, we identified activated BRAF signaling as a determinant for enzalutamide resistance. Combined pharmaceutical targeting of AR and MAPK signaling resulted in strong synergistic inhibition of cell proliferation. The association between BRAF activation and enzalutamide resistance was confirmed in two metastatic prostate cancer patients harboring activating mutations in the BRAF gene, as both patients were unresponsive to enzalutamide. Our findings suggest that co-targeting of the MAPK and AR pathways may be effective in patients with an activated MAPK pathway, particularly in patients harboring oncogenic BRAF mutations. These results warrant further investigation of the response to AR inhibitors in BRAF-mutated prostate tumors in clinical settings. [ABSTRACT FROM AUTHOR]

End of Life (EoL) products management through crude recycling methods and direct shredding causes severe threat to environment by different kinds of pollution. The environmental benefits such as reduced CO2 emissions observed through recycling are mitigated by the direct release of toxic gases. De-manufacturing through systematic disassembly operations can reduce environmental damage but it requires more input cost to work within the threshold limit value (TLV). Complete disassembly sequence planning (CDSP) methods are not given importance in de-manufacturing objectives, which produce non-optimal solutions. The objective of present work is to produce an optimal solution to extract valuable materials from the EoL products while separating the toxic elements within TLV. A multi-layered method has been proposed that consists of five different layers, namely data input layer, application layer, modification layer, implementation layer and performance layer. It requires product bill of materials (BOM) and disassembly attributes such as liaison, geometric feasibility and stability as input from the user and generates an optimal solution by suggesting permissible operations to work within TLV. The proposed method has been applied on a case study and workability at producing practically feasible optimal solution has been confirmed. The effectiveness in working has been evaluated by comparing to the existing DSP methods. The proposed method can be used as a tool to achieve maximum profits through systematic disassembly operations within TLV by supplying essential information. [ABSTRACT FROM AUTHOR]

Postchemotherapy RPLND remains an integral part of management of testicular tumours. Nerve-sparing techniques can minimize the ejaculatory dysfunction due to the procedure. We report our functional and oncological outcomes for nerve-sparing RPLND in postchemotherapy settings. We analysed data from all patients undergoing nerve-sparing PC RPLND from January 1990 to December 2013 at our institute. Antegrade ejaculation and fertility issues were determined by patient history. Nerve sparing was achieved in 30% of patients undergoing PC RPLND. Of the 33 patients who underwent nerve-sparing PC RPLND, 19 (57.8%) had antegrade ejaculation. The mean time to antegrade ejaculation was 6.8 months. After a median follow-up of 75.61 months, 5-year disease-free survival was 98%. Nerve-sparing RPLND can improve functional outcomes without increasing recurrence rates in post chemotherapy setting. [ABSTRACT FROM AUTHOR]

Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation. Gene fusions involving the ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are two truncal mutations that are mutually exclusively present in prostate cancer. Here, the authors show that mutations in SPOP render prostate tumor cells sensitive to antiandrogen therapy and that the presence of ERG promotes sensitivity to high dose of androgen and SPOP inhibition. [ABSTRACT FROM AUTHOR]

Although gastric cancer (GC) is one of the most common cancers with high incidence and mortality rates, its pathogenesis is still not elucidated. GC carcinogenesis is complicated and involved in the activation of oncoproteins and inactivation of tumor suppressors. The ubiquitin-proteasome system (UPS) is crucial for protein degradation and regulation of physiological and pathological processes. E3 ubiquitin ligases are pivotal enzymes in UPS, containing various subfamily proteins. Previous studies report that some E3 ligases, including SKP2, CUL1, and MDM2, act as oncoproteins in GC carcinogenesis. On the other hand, FBXW7, FBXL5, FBXO31, RNF43, and RNF180 exert as tumor suppressors in GC carcinogenesis. Moreover, E3 ligases modulate cell growth, cell apoptosis, and cell cycle; thus, it is complicated to confer cisplatin resistance/sensitivity in GC cells. The intrinsic and acquired cisplatin resistance limits its clinical application against GC. In this review, we explore oncogenic and tumor suppressive roles of E3 ligases in GC carcinogenesis and focus on the effects of E3 ligases on cisplatin resistance in GC cells, which will provide novel therapeutic targets for GC therapy, especially for cisplatin-resistant patients. [ABSTRACT FROM AUTHOR]

Objective: To assess the use of the cell cycle progression (CCP) score versus actual risk stratification practice in making treatment decisions for prostate cancer patients with locally adverse pathology after radical prostatectomy (RP). Patients and methods: Men with adverse pathologic features, pT3 or positive surgical margins who underwent RP in 2010–2014 at Renji hospital were retrospectively analyzed. The primary outcome was biochemical recurrence (BCR) after RP. RNA was quantified from paraffin-embedded RP specimens. The CCP score was calculated as average expression of 31 CCP genes, normalized to 15 housekeeper genes. The prognostic utility of the CCP score was assessed using Kaplan–Meier analysis and multivariable Cox proportional hazards model. Results: Among the 100 men identified, 5-year BCR-free survival for the low- (< 0), intermediate- (0–1) and high- (> 1) CCP score groups was 89.3%, 38.8%, and 12.9%, respectively. In multivariable models adjusting for clinical and pathological variables with the cancer of the prostate risk assessment post-surgical (CAPRA-S) score, both continuous CCP score [hazard ratio (HR) 1.373 per unit score, 95% confidence interval (CI) 1.006–1.874; p = 0.046) and the categorized CCP score (p < 0.001)were independent predictors of BCR. Conclusions: The present study provides insights into the role the CCP score plays in risk stratification of this cohort and in determining candidacy for deferred secondary treatment. From our perspective, the CCP score allows better stratification and can help identifying patients at lower risk of disease recurrence who could benefit from a wait-and-see policy. [ABSTRACT FROM AUTHOR]

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In recent years, remanufacturing has received increased attention as a sustainable and profitable product recovery strategy. To facilitate the remanufacturing of used product returns, factors which affect remanufacturability should be considered during the product design stage. The selection of fastening method during the product design stage is one of the critical decisions which affects the remanufacturability as well as the total cost of disassembly and re-assembly of used products. Hence, both product assembly and disassembly issues should be considered in the product design stage for the selection of fastening methods. Simultaneous consideration of product assembly and disassembly in the product design stage for the fastening method selection has not been properly addressed in previous studies. In this paper, a methodology for selecting appropriate fastening method from a remanufacturing perspective is proposed in which both product assembly and disassembly are addressed. In the proposed methodology, an optimization model is formulated with the objective of minimizing the total cost of product assembly and disassembly. The genetic algorithm is employed to solve the model. A case study on the selection of fastening method for a laptop computer is conducted to illustrate the proposed methodology and to evaluate its effectiveness. The effect of the degree of product disassembly and the demand size for remanufactured products on the total cost of product assembly and disassembly was also investigated. The results showed the proposed methodology provide significant cost savings in the total product assembly and disassembly cost. [ABSTRACT FROM AUTHOR]

Use of drug combinations that target different pathways involved in the development and progression of prostate cancer (PCa) has emerged as an alternative to overcome the resistance caused by drug monotherapies. The antiandrogen abiraterone acetate and the PI3K/Akt inhibitor NVP-BEZ235 (BEZ235) may be suitable options for the prevention of drug resistance and the inhibition of PCa progression. The aim of the present study was to evaluate whether abiraterone acetate and BEZ235 achieve superior therapeutic effects to either drug administered as monotherapy, in the early stages of PCa in an androgen-dependent system. Our study showed that each drug might impair tumor growth by reducing proliferation and increasing cell death when administered as monotherapy. However, tumor growth continued to progress with each drug monotherapy and some important side effects were related to BEZ. Conversely, when used in combination, the drugs impaired the inflammatory response, decreased hyperplastic lesions, and blocked tumor progression from premalignant to a malignant stage. Our data showed that the strategy to block the androgenic and PI3K/AKT/mTOR pathway is an effective therapeutic option and should be investigated including distinct PI3K pathway inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: To validate a previously characterized 10-gene signature in prostate cancer with implication to distinguish aggressive and indolent disease within low and intermediate patients’ risk groups.Methods: A case-control study design used to select 545 patients from the Mayo clinic tumor registry who underwent radical prostatectomy. A training set from this cohort (n = 359) was used to build a 10-gene model, based on high-dimensional discriminant analysis (HDDA10) to predict several endpoints of clinical patients’ outcome. An independent set (n = 219) from the same institution was used as validation set.Results: HDDA10 showed significant performance for predicting metastasis (Mets) (AUC 0.68, p = 6.4E - 6) and biochemical recurrence (BCR) (AUC = 0.65, p = 0.003) in the validation set outperforming Gleason grade grouping (GG) for BCR (AUC 0.57, p = 0.03) and with comparable performance for Mets endpoint (GG AUC 0.66, p = 8.1E - 5). HDDA10 prognostic significance was superior to any clinical-pathological parameter within GG2 + 3 (GS7) patients achieving an AUC of 0.74 (p = 0.0037) for BCR compared to Gleason pattern 4 (AUC 0.64) (p = 0.015) and AUC for Mets of 0.68 versus AUC of 0.65 for Gleason pattern 4 (p = 0.01). HDDA10 remained significant for both BCR and Mets in multivariate analysis, suggesting that it can be used to increase accuracy in stratifying patients eligible for active surveillance.Conclusion: HDDA10 is of added value to GG and other clinical-pathological parameters in predicting BCR and Mets endpoint, especially in the low to intermediate patients’ risk groups. HDDA10 prognostic value should be further validated prospectively in stratifying patients specifically in low to intermediate GS (GG1-2), such as active surveillance programs. [ABSTRACT FROM AUTHOR]

The phosphatidylinositol (PtdIns) family of lipids plays important roles in cell differentiation, proliferation, and migration. Abnormal expression, mutation, or regulation of their metabolic enzymes has been associated with various human diseases such as cancer, diabetes, and bipolar disorder. Recently, fluorescent derivatives have increasingly been used as chemical probes to monitor either lipid localization or enzymatic activity. However, the requirements of a good probe have not been well defined, particularly modifications on the diacylglycerol side chain partly due to challenges in generating PtdIns lipids. We have synthesized a series of fluorescent PtdIns(4,5)P (PIP) and PtdIns (PI) derivatives with various lengths of side chains and tested their capacity as substrates for PI3KIα and PI4KIIα, respectively. Both capillary electrophoresis and thin-layer chromatography were used to analyze enzymatic reactions. For both enzymes, the fluorescent probe with a longer side chain functions as a better substrate than that with a shorter chain and works well in the presence of the endogenous lipid, highlighting the importance of hydrophobicity of side chains in fluorescent phosphoinositide reporters. This comparison is consistent with their interactions with lipid vesicles, suggesting that the binding of a fluorescent lipid with liposome serves as a standard for assessing its utility as a chemical probe for the corresponding endogenous lipid. These findings are likely applicable to other lipid enzymes where the catalysis takes place at the lipid-water interface. [ABSTRACT FROM AUTHOR]

Purpose: Oncologic outcomes of patients with pT3aN0/Nx prostate cancer (PCa) with positive surgical margins (PSM) after radical prostatectomy (RP) are heterogeneous. We investigated the impact of Gleason score (GS) on biochemical recurrence (BCR) in these patients. Methods: A retrospective, multicenter study was performed on 795 patients with pT3aN0/Nx PCa with PSM after RP between January 2006 and December 2014. Clinicopathologic characteristics of patients were examined and onset of BCR was identified. Kaplan-Meier survival analysis was used to illustrate BCR-free survival (BFS) and Cox proportional hazard models were applied to identify factors predicting BCR. Results: During the mean follow-up period of 63.9 months, BCR was identified in 274 (34.5%) patients. The 5-year BFS was 56.6% in all patients. In multivariate analysis, pathologic GS was the only significant prognostic factor for BCR in patients with pT3aN0/Nx PCa with PSM (GS 6 vs. GS 7 (3 + 4), P = 0.047; vs. GS 7 (4 + 3), P = 0.007, and vs. GS 8-10, P < 0.001). When patients were stratified according to GS, 5-year BFS was 78.6% in GS 6, 66.2% in GS 7 (3 + 4), 51.1% in GS 7 (4 + 3) and 35.5% in GS 8-10. Conclusions: In patients with pT3aN0/Nx with PSM after RP, pathologic GS is the sole independent predictor for risk stratification of BCR. These findings might be used to determine the risk and timing of BCR and to help counsel patients regarding treatment strategy and prognosis of disease on an individual basis. [ABSTRACT FROM AUTHOR]