Therapeutic Target For Prostate Cancer Research Articles

Inhibition of aldo-keto reductase 1C3 overcomes gemcitabine/cisplatin resistance in bladder cancer

Systemic chemotherapy with gemcitabine and cisplatin (GC) has been used for the treatment of bladder cancer in which androgen receptor (AR) signaling is suggested to play a critical role. However, its efficacy is often limited, and the prognosis of patients who develop resistance is extremely poor. Aldo-keto reductase 1C3 (AKR1C3), which is responsible for the production of a potent androgen, 5α-dihydrotestosterone (DHT), by the reduction of 5α-androstane-3α,17β-dione (5α-Adione), has been attracting attention as a therapeutic target for prostate cancer that shows androgen-dependent growth. By contrast, the role of AKR1C3 in bladder cancer remains unclear. In this study, we examined the effect of an AKR1C3 inhibitor on androgen-dependent proliferation and GC sensitivity in bladder cancer cells. 5α-Adione treatment induced the expression of AR and its downstream factor ETS-domain transcription factor (ELK1) in both T24 cells and newly established GC-resistant T24GC cells, while it did not alter AKR1C3 expression. AKR1C3 inhibitor 2j significantly suppressed 5α-Adione-induced AR and ELK1 upregulation, as did an AR antagonist apalutamide. Moreover, the combination of GC and 2j in T24GC significantly induced apoptotic cell death, suggesting that 2j could enhance GC sensitivity. Immunohistochemical staining in surgical specimens further revealed that strong expression of AKR1C3 was associated with significantly higher risks of tumor progression and cancer-specific mortality in patients with muscle-invasive bladder cancer. These results suggest that AKR1C3 inhibitors as adjunctive agents enhance the efficacy of GC therapy for bladder cancer.

Bioanalysis of the Ex Vivo Labile PACE4 Inhibitory Peptide Ac-[d-Leu]LLLRVK-Amba in Whole Blood Using Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Quantification.

The calcium-dependent serine endoprotease PACE4 is evaluated as a therapeutic target for prostate cancer. The peptide Ac-[d-Leu]LLLRVK-amba inhibits PACE4 with high affinity and has shown efficacy in preclinical mice xenograft models of prostate cancer. To support in vivo examinations of the potential therapeutic peptide Ac-[d-Leu]LLLRVK-amba, we established a highly sensitive assay for its quantification in mouse whole blood microsamples based on UPLC-MS/MS determination. Ac-[d-Leu]LLLRVK-amba was very labile during sample processing, which was particularly pronounced in plasma. High resolution mass spectrometric investigations of the metabolism/degradation in plasma revealed that no peptide bond hydrolysis generated products were formed, leaving the cause of the observed consumption of the peptide elusive. As a consequence, whole-blood quantification was developed relying on the immediate snap-freezing of blood samples after collection and immediate sample processing after serial thawing to ensure accurate and reliable quantification. The assay was validated according to the applicable recommendations of the FDA and EMA in a range of 10-10,000 ng/mL and applied to determine the pharmacokinetics of Ac-[d-Leu]LLLRVK-amba after intravenous and intraperitoneal administration to mice. Individual pharmacokinetic profiles were assessed using four microsamplings per animal. Intraperitoneal absorption was found to be efficient, demonstrating that this well-manageable route of administration is feasible for preclinical efficacy experiments with Ac-[d-Leu]LLLRVK-amba.

Tumor suppressor miR-361-3p inhibits prostate cancer progression through Gli1 and AKT/mTOR signaling pathway

BackgroundThe primary challenge in prostate cancer (PCa) is tumor metastasis, which seriously affects the survival time of patients. Growing evidence suggests that microRNAs play a crucial regulatory role in various malignancies and that the tumor suppressor miR-361-3p is responsible for regulating migration, proliferation, and invasion in different cancer types. However, the underlying regulatory mechanism of miR-361-3p in PCa remains unknown. MethodsThe expression of miR-361-3p in PCa cells was analyzed using quantitative real time-polymerase chain reaction. The clinical utility of miR-361-3p in PCa was evaluated using in vitro assays. The mechanism of action of miR-361-3p was investigated using western blotting, luciferase reporter assays, immunofluorescence, and rescue studies. ResultsThe function, invasiveness, migration, and proliferation of PCa cells, as well as epithelial-mesenchymal transition (EMT), were aided by the downregulation of miR-361-3p, whereas its overexpression exerted the opposite effect. Repression of glioma-associated oncogene homolog 1 (Gli1) expression by miR-361-3p led to activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathway, triggering EMT and promoting PCa metastasis. ConclusionsDownregulation of miR-361-3p along the Gli1 axis promoted tumor malignancy. Collectively, the results of this study imply that miR-361-3p has the potential to be both a biomarker and therapeutic target in PCa.

Abstract C054: Association of fatty acid synthase expression with FASN gene methylation and self-identified race in prostate cancer

Abstract Fatty acid synthase (FASN) catalyzes the synthesis of long-chain saturated fatty acids and is overexpressed during prostatic tumorigenesis; however, the mechanism of this upregulation remains unclear and could include gene amplification, epigenetic regulation or regulation by androgen receptor (AR). Though FASN is an attractive therapeutic target in prostate cancer and several clinical trials of FASN inhibitors are underway, prior studies have suggested racial disparities in FASN copy number and FASN protein expression exist in primary prostate cancer, which may have implications for the therapeutic efficacy of FASN inhibitors. FASN gene amplification may be more common in prostate cancers from self-identified Black (BL) patients than their White (WH) counterparts, and a recent study has suggested that FASN protein expression is also higher among primary prostate tumors from BL compared to WH men due to changes in the AR cistrome. Here, we examine FASN protein expression as measured by digitally quantified immunohistochemistry assay and reverse phase protein array analysis or FASN gene expression, comparing it to gene CpG methylation pattern by InfiniumEPIC profiling and whole genome bisulfite sequencing (WGBS) across multiple racially diverse primary and metastatic prostate cancer cohorts, including more than 1000 tumors. We demonstrate that the FASN gene body is hypomethylated and overexpressed in primary prostate tumors compared to benign tissue. FASN gene methylation shows a significant inverse correlation with FASN protein and gene expression in both primary and metastatic prostate cancer. However, in contrast to previous studies, we find no significant association of FASN expression or methylation with self-identified race or genetic ancestry in models that include ERG gene fusion status across two independent primary tumor cohorts. Taken together, these data support a potential epigenetic mechanism for FASN regulation in the prostate and suggest that FASN inhibitors may be equally efficacious in both BL and WH men with prostate cancer. Citation Format: Oluwademilade Dairo, Lia DePaula Oliveira, Ethan Schaffer, Thiago Vidotto, Adrianna Amaral De Aragao Mendes, Jiayun Lu, Jessica Hicks, Adam G. Sowalsky, Angelo M. De Marzo, Corrine E. Joshu, Brian Hanratty, Karen S. Sfanos, William B. Isaacs, Michael C. Haffner, Tamara L. Lotan. Association of fatty acid synthase expression with FASN gene methylation and self-identified race in prostate cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C054.

MotifHub: Detection of trans-acting DNA motif group with probabilistic modeling algorithm

BackgroundTrans-acting factors are of special importance in transcription regulation, which is a group of proteins that can directly or indirectly recognize or bind to the 8–12 bp core sequence of cis-acting elements and regulate the transcription efficiency of target genes. The progressive development in high-throughput chromatin capture technology (e.g., Hi-C) enables the identification of chromatin-interacting sequence groups where trans-acting DNA motif groups can be discovered. The problem difficulty lies in the combinatorial nature of DNA sequence pattern matching and its underlying sequence pattern search space. MethodHere, we propose to develop MotifHub for trans-acting DNA motif group discovery on grouped sequences. Specifically, the main approach is to develop probabilistic modeling for accommodating the stochastic nature of DNA motif patterns. ResultsBased on the modeling, we develop global sampling techniques based on EM and Gibbs sampling to address the global optimization challenge for model fitting with latent variables. The results reflect that our proposed approaches demonstrate promising performance with linear time complexities. ConclusionMotifHub is a novel algorithm considering the identification of both DNA co-binding motif groups and trans-acting TFs. Our study paves the way for identifying hub TFs of stem cell development (OCT4 and SOX2) and determining potential therapeutic targets of prostate cancer (FOXA1 and MYC). To ensure scientific reproducibility and long-term impact, its matrix-algebra-optimized source code is released at http://bioinfo.cs.cityu.edu.hk/MotifHub.

Circ_0082878 contributes to prostate cancer progression via the miR-455-3p/WTAP axis.

Circ_0082878 has been found to be strongly expressed in prostate cancer (PCa). However, its roles and potential mechanism in PCa have not been investigated. This study aims to clarify it. RNase R digestion method was adopted for verifying the circular structure of circ_0082878. RT-qPCR assay is aimed to detect the expressions of circ_0082878, miR-455-3p and WTAP in PCa tissues and cells. For identifying cell proliferation, migration and invasion abilities, CCK-8 and transwell assay were used. To show the correlation between miR-455-3p and WTAP or circ_0082878, the luciferase reporter gene, RNA RIP and RNA pull-down experiments were employed. We employed western blot to detect protein level of WTAP. In addition, the impact of circ_0082878 on PCa cells in vivo was also studied. It was found that circ_0082878 and WTAP were highly expressed in PCa tissues and cells, whereas miR-455-3p was lowly expressed. Inhibition of circ_0082878 restrained the growth of PCa in vitro and in vivo. Regarding mechanism, miR-455-3p was the target of circ_0082878, and WTAP was the target of miR-455-3p. Circ_0082878 could downregulate the level of miR-455-3p, and inhibiting of miR-455-3p expression could partially eliminate the inhibitory impact of low expression of circ_0082878 on the proliferation and migration of PCa cells. Additionally, over-expression of miR-455-3p resulted in the reduced level of WTAP, and WTAP over-expression counteracted the tumor suppressive impact of miR-455-3p in PCa cells. Moreover, the obtained findings indicated that circ_0082878 may exert tumor-promoting activity in PCa via sponging miR-455-3p and then upregulating WTAP. This indicates that the circ_0082878/miR-455-3p/WTAP axis can probably become the possible therapeutic target for PCa.

SND1 binds to ERG and promotes tumor growth in genetic mouse models of prostate cancer

SND1 and MTDH are known to promote cancer and therapy resistance, but their mechanisms and interactions with other oncogenes remain unclear. Here, we show that oncoprotein ERG interacts with SND1/MTDH complex through SND1’s Tudor domain. ERG, an ETS-domain transcription factor, is overexpressed in many prostate cancers. Knocking down SND1 in human prostate epithelial cells, especially those overexpressing ERG, negatively impacts cell proliferation. Transcriptional analysis shows substantial overlap in genes regulated by ERG and SND1. Mechanistically, we show that ERG promotes nuclear localization of SND1/MTDH. Forced nuclear localization of SND1 prominently increases its growth promoting function irrespective of ERG expression. In mice, prostate-specific Snd1 deletion reduces cancer growth and tumor burden in a prostate cancer model (PB-Cre/Ptenflox/flox/ERG mice), Moreover, we find a significant overlap between prostate transcriptional signatures of ERG and SND1. These findings highlight SND1’s crucial role in prostate tumorigenesis, suggesting SND1 as a potential therapeutic target in prostate cancer.

Novel Insights on the Role of Epigenetics in Androgen Receptor's Expression in Prostate Cancer.

The androgens/androgen receptor (AR) axis is the main therapeutic target in prostate cancer (PCa). However, while initially responsive, a subset of tumors loses AR expression through mechanisms putatively associated with epigenetic modifications. In this study, we assessed the link between the presence of CpG methylation in the 5'UTR and promoter regions of AR and loss of AR expression. Hence, we characterized and compared the methylation signature at CpG resolution of these regulatory regions in vitro, both at basal levels and following treatment with 5-aza-2-deoxycytidine (DAC) alone, or in combination with Trichostatin A (TSA). Our results showed heterogeneity in the methylation signature of AR negative cell lines and pinpointed the proximal promoter region as the most consistently methylated site in DU-145. Furthermore, this region was extremely resistant to the demethylating effects of DAC and was only significantly demethylated upon concomitant treatment with TSA. Nevertheless, no AR re-expression was detected at the mRNA or protein level. Importantly, after treatment, there was a significant increase in repressive histone marks at AR region 1 in DU-145 cells. Altogether, our data indicate that AR region 1 genomic availability is crucial for AR expression and that the inhibition of histone methyltransferases might hold promise for AR re-expression.

Identification of the mitochondrial protein POLRMT as a potential therapeutic target of prostate cancer

RNA polymerase mitochondria (POLRMT) is essential for mitochondrial transcription machinery and other mitochondrial functions. Its expression and potential functions in prostate cancer were explored here. The Cancer Genome Atlas prostate cancer cohort (TCGA PRAD) shows that POLRMT mRNA expression is upregulated in prostate cancer tissues and POLRMT upregulation is correlated with poor patients’ survival. POLRMT mRNA and protein levels were upregulated in local prostate cancer tissues and different primary/immortalized prostate cancer cells. Genetic depletion of POLRMT, using viral shRNA or CRISPR/Cas9 gene editing methods, impaired mitochondrial functions in prostate cancer cells, leading to mitochondrial depolarization, oxidative stress, mitochondria complex I inhibition, and ATP depletion. Moreover, POLRMT depletion resulted in robust inhibition of prostate cancer cell viability, proliferation, and migration, and provoked apoptosis. Conversely, prostate cancer cell proliferation, migration, and ATP contents were strengthened following ectopic POLRMT overexpression. In vivo, intratumoral injection of POLRMT shRNA adeno-associated virus impeded prostate cancer xenograft growth in nude mice. POLRMT silencing, oxidative stress, and ATP depletion were detected in POLRMT shRNA-treated prostate cancer xenograft tissues. IMT1 (inhibitor of mitochondrial transcription 1), the first-in-class POLRMT inhibitor, inhibited prostate cancer cell growth in vitro and in vivo. Together, overexpressed POLRMT is an important mitochondrial protein for prostate cancer cell growth, representing a novel and promising diagnostic and therapeutic oncotarget.

Exosome miRNA-203 promotes M1 macrophage polarization and inhibits prostate cancer tumor progression.

Prostate cancer (PCa) is a prevalent malignant neoplasm affecting the male reproductive system globally. However, the diagnostic and therapeutic approaches fall short of meeting the demands posed by PCa. Poor expression of miRNA-203 (miR-203) within PCa tissues and cells implies its potential utility as a diagnostic indicator for PCa. Exosomes (Exo), membranous vesicles released by various cells, are rich reservoirs of miRNAs. However, the presence of miR-203 presents within Exo derived from PCa cells remains unclarified. In this study, Exo was isolated from urine specimens collected from clinical PCa patients and LNCaP cells to detect miR-203 expression. Meanwhile, the impact of overexpressed miR-203 on M0 macrophages (mø) was analyzed. Subsequently, alterations in the proliferative, migratory, and invasive capacities of LNCaP cells were examined within a co-culture system featuring elevated miR-203 levels in both macrophages and LNCaP cells. Furthermore, the repercussions of miR-203 upregulation or inhibition were explored in a murine PCa tumor model. The results revealed that Exo manifested a circular or elliptical morphology, encapsulating a phospholipid bilayer approximately 100nm in diameter. Notably, Exo readily infiltrated, with both Exo and miR-203-overexpressing Exo prompting macrophage polarization toward the M1 subtype. In the co-culture system, miR-203 exhibited pronounced suppression of LNCaP cell proliferation, migration, and invasion, while concurrently fostering apoptosis as compared with the LNCaP group (Control). In vivo experiments further disclosed that miR-203 greatly inhibited the growth of PCa tumors in nude mice. Markedly heightened expression of M1 macrophage markers such as IL-1β, IL-6, IL-12, CXCL9, and CXCL10 was observed within the tumor microenvironment following miR-203 intervention, as opposed to the model group. However, the introduction of miR-203 antagomir led to a reversal in tumor growth trends. This investigation indicates the presence of miR-203 within the urine of PCa patients and Exo originating from cells, and that miR-203 exerted antitumor effect by facilitating M1 macrophage polarization. Our study furnishes valuable insights into the potential applicability of miR-203 as a diagnostic biomarker and therapeutic target for PCa.

Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase.

The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression. See related commentary by Mishra et al., p. 4008.

SAT022 A Mechanism Of Resistance To Novel Inhibitors Of The N-Terminal Domain Of Androgen Receptor

Abstract Disclosure: J. Setiawan: None. N.R. Mawji: None. A.H. Tien: None. R.J. Andersen: Stock Owner; Self; ESSA Pharma. M.D. Sadar: Stock Owner; Self; ESSA Pharma. Background: Androgen receptor (AR) is a steroid hormone receptor and a major therapeutic target in prostate cancer. Antiandrogen therapies directed at the AR C-terminal ligand-binding domain (LBD) provide initial benefit to patients with advanced prostate cancer, but they eventually progress to lethal metastatic castration-resistant prostate cancer (CRPC). AR N-terminal domain (NTD) inhibitors are a novel class of antagonists that were developed to overcome resistance mechanisms related to the AR-LBD, including splice variants lacking the LBD (AR-V7). While mutations in the AR-LBD have been well-characterized, the impact of NTD mutations on AR transcriptional activity and drug efficacy remains unclear. The mutation W435L was discovered from clinical samples of prostate cancer from patients treated with antiandrogens. This mutation stabilizes interaction between the AR’s NTD and LBD (N/C interaction) to increase AR transcriptional activity. Tryptophan residues W435 and W397 in AR NTD are essential in the binding site for the AR-NTD inhibitor EPI-7386 that is currently in clinical trials. We hypothesize that tryptophan mutations within the EPI-7386 binding site of AR are a potential mechanism of resistance. Methods: Site-directed mutagenesis was used to create expression vectors with W435 and W397 point mutations in AR. Plasmids were transfected into AR-negative CV-1 cells to compare the transcriptional activity of wild-type (WT) versus mutant ARs. IC50s for each inhibitor were generated for androgen-induced reporter gene constructs. A mammalian two-hybrid system assay was used to assess the impact of inhibitors and AR mutations on N/C interaction. Results: The AR-W435L mutation led to higher IC50s to inhibit androgen-induced MMTV-luciferase activity by NTD inhibitors and antiandrogens. Differences in N/C interaction were observed between WT and mutant ARs treated with EPI-7386. Importantly, the ability of another EPI analog, EPI-7170, to decrease AR-N/C interaction was not significantly impacted by W435L. These data support that loss of efficacy with EPI-7386 is not across the entire class of EPI analogs and may be specific to EPI-7386. Conclusion: Tryptophan mutations in the EPI-7386 binding site are predictive of resistance to this specific antagonist and do not broadly apply to the entire class of EPI analogs. Key differences were revealed between AR-LBD and AR-NTD inhibitors that support the recruitment of different tau regions in the NTD. Presentation: Saturday, June 17, 2023

THU550 The Splicing Factor SRSF6 Regulates Androgen Receptor Activity And Represents A Potential Therapeutic Target In Prostate Cancer

Abstract Disclosure: R.M. Luque: None. A.J. Montero-Hidalgo: None. E. Gomez-Gomez: None. D. Olmos: None. M.D. Gahete: None. J.M. Jimenez-Vacas: None. Background: Prostate cancer (PCa) is the fifth leading cause of cancer-related death worldwide. Finding novel therapeutic strategies to tackle PCa, especially its most advanced phenotype [i.e., castration-resistant prostate cancer (CRPC)], is urgently needed. In this sense, although the dysregulation of the splicing process has emerged as a distinctive feature of advanced PCa, the potential role that splicing regulators may play in this disease remain poorly understood. In this study, we aimed to analyse the levels, pathophysiological role and associated molecular landscape of the splicing factor SRSF6 in PCa. Methods: SRSF6 levels (mRNA, protein and CNA) were interrogated in seven well-characterized cohorts of PCa patients and in the Hi-MYC transgenic model. The effect of SRSF6 overexpression and silencing was tested in vitro (proliferation, migration, colony- and tumorspheres-formation) and in vivo (tumor growth of xenograft tumours). RNAseq was performed in 22Rv1 cells to analyse splicing and gene expression changes in response to SRSF6 silencing. Findings: Our results showed that SRSF6 levels (mRNA/protein) are upregulated in PCa vs non-tumour prostate samples, linked to clinical parameters of tumour-aggressiveness (e.g., Gleason score, T-stage, perineural infiltration, metastasis at diagnosis), and associated with poor prognosis (i.e., shorter disease-free survival time) in PCa patients. Moreover, SRSF6-overexpression increased, while its silencing decreased, functional parameters of aggressiveness in vitro and tumour growth in vivo. Mechanistically, SRSF6 modulation resulted in dysregulation of Androgen-Receptor (AR) activity through transcriptional control of APPBP2 and TOP2B. Discussion: SRSF6 could represent a new therapeutic target to inhibit persistent AR-signalling in advanced PCa. Funding: Spanish Ministry of Science, Innovation, and Universities (PID2019-105564RB-I00, FPU18/02485), Health Institute Carlos III (DTS20-00050), and CIBERobn. Presentation: Thursday, June 15, 2023

Proteome-wide mendelian randomization study implicates therapeutic targets in common cancers

BackgroundThe interest in targeted cancer therapies has been growing rapidly. While numerous cancer biomarkers and targeted treatment strategies have been developed and employed, there are still significant limitations and challenges in the early diagnosis and targeted treatment of cancers. Accordingly, there is an urgent need to identify novel targets and develop new targeted drugs.MethodsThe study was conducted using combined cis-Mendelian randomization (cis-MR) and colocalization analysis. We analyzed data from 732 plasma proteins to identify potential drug targets associated with eight site-specific cancers. These findings were further validated using the UK Biobank dataset. Then, a protein–protein interaction network was also constructed to examine the interplay between the identified proteins and the targets of existing cancer medications.ResultsThis MR analysis revealed associations between five plasma proteins and prostate cancer, five with breast cancer, and three with lung cancer. Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. Our study indicatied that genetically predicted KDELC2 (OR: 0.89, 95% CI 0.86–0.93) and TNFRSF10B (OR: 0.74, 95% CI 0.65–0.83) are inversely associated with prostate cancer. Furthermore, we observed an inverse association between CPNE1 (OR: 0.96, 95% CI 0.94–0.98) and breast cancer, while PDIA3 (OR: 1.19, 95% CI 1.10–1.30) were found to be associated with the risk of breast cancer. In addition, we also propose that SPINT2 (OR: 1.05, 95% CI 1.03–1.06), GSTP1 (OR: 0.82, 95% CI 0.74–0.90), and CTSS (OR: 0.91, 95% CI 0.88–0.95) may serve as potential therapeutic targets in prostate cancer. Similarly, GDI2 (OR: 0.85, 95% CI 0.80–0.91), ISLR2 (OR: 0.87, 95% CI 0.82–0.93), and CTSF (OR: 1.14, 95% CI 1.08–1.21) could potentially be targets for breast cancer. Additionally, we identified SFTPB (OR: 0.93, 95% CI 0.91–0.95), ICAM5 (OR: 0.95, 95% CI 0.93–0.97), and FLRT3 (OR: 1.10, 95% CI 1.05–1.15) as potential targets for lung cancer. Notably, TNFRSF10B, GSTP1, and PDIA3 were found to interact with the target proteins of current medications used in prostate or breast cancer treatment.ConclusionsThis comprehensive analysis has highlighted thirteen plasma proteins with potential roles in three site-specific cancers. Continued research in this area may reveal their therapeutic potential, particularly KDELC2, TNFRSF10B, CPNE1, and PDIA3, paving the way for more effective cancer treatments.

Antitumor activity of alkylphospholipid edelfosine in prostate cancer models and endoplasmic reticulum targeting

Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men worldwide. While the five-year survival in local and regional prostate cancer is higher than 99%, it falls to about 28% in advanced metastatic prostate cancer. The ether lipid edelfosine is considered the prototype of a family of promising antitumor drugs collectively named as alkylphospholipid analogs. Here, we found that edelfosine was the most potent alkylphospholipid analog in inducing apoptosis in three different human prostate cancer cell lines (LNCaP, PC3, and DU145) with distinct androgen dependency, and differing in tumor suppressor phosphatase and tensin homolog (PTEN) and p53 status. Edelfosine accumulated in the endoplasmic reticulum of prostate cancer cells, leading to endoplasmic reticulum stress and cell death in the three prostate cancer cells. Inhibition of autophagy potentiated the pro-apoptotic activity of edelfosine in LNCaP and PC3 cells, where autophagy was induced as a survival response. Edelfosine induced a slight and transient inhibition of AKT in PTEN-negative LNCaP and PC3 cells, but not in PTEN-positive DU145 cells. Daily oral administration of edelfosine in murine prostate restricted AKT kinase transgenic mice, expressing active AKT in a prostate-specific manner, and in a DU145 xenograft mouse model resulted in significant tumor regression and apoptosis in tumor cells. Taken together, these results show a significant in vitro and in vivo antitumor activity of edelfosine against prostate cancer, and highlight the endoplasmic reticulum as a novel and promising therapeutic target in prostate cancer.

Association betweenthe Estrogen receptor β rs1256049 polymorphism and prostate cancer risk:a meta-analysis.

The Estrogen receptor β (ESR-β) gene is suggested to have a growth inhibitory role in prostate tissue and was proposed as a new therapeutic target for prostate cancer (PCa). Precedent studies have investigated the association between the ESR-β rs1256049 polymorphism and PCa but findings were inconsistent. Thus, this meta-analysis was performed to assess whether the ESR-β rs1256049 polymorphism is associated with an increased susceptibility to PCa. Eligible studies published before February 5, 2022 were systematically searched in PubMed, Web of Science, ScienceDirect and Google Scholar databases. The sample set was extracted from 11 case-control studies involving 9390 cases and 10057 controls for the association between ESR-β rs1256049 polymorphism and PCa susceptibility. In our overall meta-analysis, no significant association between rs1256049 and PCa risk was found under all genetic models. In subgroup analysis according to ethnicity, Asians, had a significantly decreased cancer risk based on both the heterozygote genetic model (OR =0.75, 95% CI =[0.63, 0.89] P =0.01) and the dominant model (OR =0.80, 95% CI [0.69, 0.94] P =0.01). For the Caucasian group, there was a significantly increased risk observed in the allelic model (OR =1.17, 95% CI =[1.04, 1.32] P =0.01), heterozygote model (OR =1.15, 95% CI =[1.01, 1.31] P =0.03) and the dominant model (OR =1.17, 95% CI =[1.03, 1.32] P =0.01). Our results demonstrate that ESR-β r1256049 polymorphism may play a possible promising effect in PCa in Caucasians and a protective factor in Asians.

LncRNA UBE2R2-AS1, as prognostic marker, promotes cell proliferation and EMT in prostate cancer.

Long noncoding RNA ubiquitin-conjugating enzyme E2 R2 antisense RNA 1 (UBE2R2-AS1) has been recently reported to participate in the progression of tumors, including glioma and liver cancer. However, the roles of UBE2R2-AS1 in prostate cancer (PC) remained poorly understood. The expression of UBE2R2-AS1 was determined in tumor tissues and paired adjacent tissues from PC patients using quantitative reverse transcription PCR analysis. Correlation between UBE2R2-AS1 expression and clinicopathological parameters and overall survival were investigated by Chi-square test and Kaplan-Meier method analysis. The in vitro experiments, including CCK-8 assay, colony formation, flow cytometry and transwell assay were performed to investigate the functional role of UBE2R2-AS1 knockdown or overexpression on PC cell lines (PC-3 and DU145). Related protein expression levels were measured by western blot analysis. Our data showed that UBE2R2-AS1 expression was significantly upregulated in PC tissues compared with that in adjacent tissues. The high levels of UBE2R2-AS1 were associated with high Gleason score, advanced clinical T stage, lymph node metastasis and poor prognosis. Knockdown of UBE2R2-AS1 suppressed cell proliferation, migration and invasion, induced cell cycle G0/G1 arrest and apoptosis in PC cells, along with decreased expression of PCNA, CDK4, Cyclin D1, Bcl-2, N-cadherin and Vimentin, and increased E-cadherin expression. Overexpression of UBE12R2-AS1 obtained the opposite results in PC cells. Our findings suggest that UBE2R2-AS1 might be a potential diagnostic and/or therapeutic target in PC.

New insights into lipid metabolism and prostate cancer (Review).

Prostate cancer (PCa) is the most common malignant tumor of the male urological system and poses a severe threat to the survival of middle‑aged and elderly males worldwide. The development and progression of PCa are affected by a variety of biological processes, including proliferation, apoptosis, migration, invasion and the maintenance of membrane homeostasis of PCa cells. The present review summarizes recent research advances in lipid (fatty acid, cholesterol and phospholipid) metabolic pathways in PCa. In the first section, the metabolism of fatty acids is highlighted, from formation to catabolism and associated proteins. Subsequently, the role of cholesterol in the pathogenesis and evolution of PCa is described in detail. Finally, the different types of phospholipids and their association with PCa progression is also discussed. In addition to the impact of key proteins of lipid metabolism on PCa growth, metastasis and drug resistance, the present review also summarizes the clinical value of fatty acids, cholesterol and phospholipids, as diagnostic and prognostic indicators and therapeutic targets in PCa.

Cell-by-cell quantification of the androgen receptor in benign and malignant prostate leads to a better understanding of changes linked to cancer initiation and progression.

The androgen receptor (AR) plays a crucial role in the development and homeostasis of the prostate and is a key therapeutic target in prostate cancer (PCa). The gold standard therapy for advanced PCa is androgen deprivation therapy (ADT), which targets androgen production and AR signaling. However, resistance to ADT develops via AR-dependent and AR-independent mechanisms. As reports on AR expression patterns in PCa have been conflicting, we performed cell-by-cell AR quantification by immunohistochemistry in the benign and malignant prostate to monitor changes with disease development, progression, and hormonal treatment. Prostates from radical prostatectomy (RP) cases, both hormone-naïve and hormone-treated, prostate tissues from patients on palliative ADT, and bone metastases were included. In the normal prostate, AR is expressed in >99% of luminal cells, 51% of basal cells, and 61% of fibroblasts. An increase in the percentage of AR negative (%AR-) cancer cells along with a gradual loss of fibroblastic AR were observed with increasing Gleason grade and hormonal treatment. This was accompanied by a parallel increase in staining intensity of AR positive (AR+) cells under ADT. Staining AR with N- and C-terminal antibodies yielded similar results. The combination of %AR- cancer cells, %AR- fibroblasts, and AR intensity score led to the definition of an AR index, which was predictive of biochemical recurrence in the RP cohort and further stratified patients of intermediate risk. Lastly, androgen receptor variant 7 (ARV7)+ cells and AR- cells expressing neuroendocrine and stem markers were interspersed among a majority of AR+ cells in ADT cases. Altogether, the comprehensive quantification of AR expression in the prostate reveals concomitant changes in tumor cell subtypes and fibroblasts, emphasizing the significance of AR- cells with disease progression and palliative ADT.

LINC01002 Targets miR-650/FLNA Pathway to Suppress Prostate Cancer Progression

Introduction: In view of the vital implication of long noncoding RNAs in tumorigenesis, we possess the aim to determine the action effects and mechanisms of LINC01002 in prostate cancer (PCa). Methods: Expression level of LINC01002, miR-650, or filamin A (FLNA) in PCa tissues and cells was assessed using quantitative real-time PCR or Western blotting. Cell proliferative and migratory capacities were investigated by Cell Counting Kit-8 (CCK-8) and wound healing assays. Cell apoptosis was investigated by the levels of Bax and Bcl-2. Xenograft models were constructed to testify the role of LINC01002 in vivo. The anticipated binding of miR-650 to LINC01002 or FLNA was confirmed by dual-luciferase reporter or RNA binding protein immunoprecipitation assays. Results: Relatively poor expression of LINC01002 and FLNA, and high expression of miR-650 were identified in PCa tumor specimens and cells. Ectopic LINC01002 expression restrained PCa cell proliferation/migration and provoked apoptosis in vitro, and blocked solid tumor growth in Xenograft models. MiR-650 was directly targeted by LINC01002, and it also directly bound to FLNA. MiR-650 reintroduction in PCa cells overexpressing LINC01002 or FLNA partly reversed the anticancer effects of LINC01002 or FLNA overexpression, thus recovering PCa cell proliferation/migration and repressing apoptosis. Conclusion: LINC01002 deregulation was linked to PCa development. LINC01002 exerted potential anticancer effects in PCa via targeting the miR-650/FLNA pathway, which, at least in part, provided a basis for the involvement of LINC01002 as a therapeutic target in PCa.