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Background Radiation therapy (RT) with androgen deprivation therapy (ADT) is an effective therapy to suppress the locally advanced prostate cancer (PCa). However, we unexpectedly found that RT could also induce the androgen receptor splice variant 7 (ARv7) expression to decrease the radiosensitivity . Methods The study was designed to target ARv7 expression with Quercetin or ARv7-shRNA that leads to enhancing and increasing the radiation sensitivity to better suppress the PCa that involved the modulation of the circNHS/miR-512-5p/XRCC5 signaling. Results Mechanism studies revealed that RT-induced ARv7 may function via altering the circNHS/miR-512-5p/XRCC5 signaling to decrease the radiosensitivity . Results from preclinical studies using multiple in vitro cell lines and in vivo mouse models concluded that combining RT with the small molecule of Quercetin to target full-length AR and ARv7 could lead to better efficacy to suppress PCa progression. Conclusion Together, these results suggest that ARv7 may play key roles to alter the PCa radiosensitivity, and targeting this newly identified ARv7 mediated circNHS/miR-512-5p/XRCC5 signaling with Quercetin may help physicians to develop a novel RT to better suppress the progression of PCa.

Fatty acid-binding protein 5 (FABP5) and androgen receptor (AR) are critical promoters of prostate cancer. In the present study, the effects of knocking out the FABP5 or AR genes on malignant characteristics of prostate cancer cells were investigated, and changes in the expression of certain key proteins in the FABP5 (or AR)-peroxisome proliferator activated receptor-γ (PPARγ)-vascular endothelial growth factor (VEGF) signaling pathway were monitored. The results obtained showed that FABP5- or AR-knockout (KO) led to a marked suppression of the malignant characteristics of the cells, in part, through disrupting this signaling pathway. Moreover, FABP5 and AR are able to interact with each other to regulate this pathway, with FABP5 controlling the dominant AR splicing variant 7 (ARV7), and AR, in return, regulates the expression of FABP5. Comparisons of the RNA profiles revealed the existence of numerous differentially expressed genes (DEGs) comparing between the parental and the FABP5- or AR-KO cells. The six most abundant changes in DEGs were found to be attributable to the transition from androgen-responsive to androgen-unresponsive, castration-resistant prostate cancer (CRPC) cells. These findings have provided novel insights into the complex molecular pathogenesis of CRPC cells, and have demonstrated that interactions between FABP5 and AR contribute to the transition of prostate cancer cells to an androgen-independent state. Moreover, gene enrichment analysis revealed that the most highly enriched biological processes associated with the DEGs included those responsive to fatty acids, cholesterol and sterol biosynthesis, as well as to lipid and fatty acid transportation. Since these pathways regulated by FABP5 or AR may be crucial in terms of transducing signals for cancer cell progression, targeting FABP5, AR and their associated pathways, rather than AR alone, may provide a new avenue for the development of therapeutic strategies geared towards suppressing the malignant progression to CRPC cells.

Background Androgen deprivation therapy (ADT) induces cellular senescence and tumor stasis, thus serving as the standard treatment for prostate cancer (PCa). However, continuous suppression of canonical androgen receptor signaling actually leads to the switch from androgen-responsive growth to androgen-independent growth, contributing to “escape” from this ADT-induced senescence (AIS) and, subsequently, the development of castration-resistant prostate cancer (CRPC). Unfortunately, the mechanism underlying this phenomenon remains elusive. Results In this study, we demonstrated that androgen receptor splicing variant 7 (ARv7), a dominant factor mediating abnormal AR signaling and ADT resistance, is closely associated with outgrowth from AIS of PCa cells. Mechanistically, ARv7 binds to the promoter of SKP2 , activating its transcription, and then promotes the proteasomal degradation of the cell cycle regulator p27 and G1/S transition. In addition, we applied bioinformatic and in vitro analyses to show that SKP2 expression level is dramatically inhibited upon ADT, but its reactivation is one key step during the establishment of CRPC. Finally, we also demonstrated that SKP2 inhibitor treatment can significantly inhibit the growth of androgen-independent cell lines and enhance the efficacy of ADT. Conclusions Our work reveals a novel role of ARv7 in regulating AIS and suggests that targeting the ARv7/SKP2/p27 axis could be a potential strategy to delay disease progression to the CRPC state during prolonged ADT.

Extrachromosomal circular DNAs (eccDNAs) are circular, double-stranded DNA molecules ubiquitously present across various organisms, playing a critical role in tumorigenesis and tumor progression. However, their precise contribution to prostate cancer (PCa) remains incompletely understood. To elucidate the function of eccDNAs in PCa, eccDNA sequencing and annotation were performed in PCa tissues and cell lines using Circle-seq. Amplified genes on eccDNAs were identified by cross-referencing annotated eccDNA-associated genes with those overexpressed in PCa based on TCGA data. Furthermore, eccDNA profiles were compared between Enzalutamide-sensitive and -resistant cell lines to investigate their role in resistance mechanisms. Notably, VAV2 was detected on both linear and circular DNA, as confirmed by PCR and Sanger sequencing. Functional analyses demonstrated that VAV2 overexpression promotes PCa proliferation and metastasis by activating the PAK1/AKT signaling pathway through PAK1 phosphorylation. Additionally, VAV2 contributes to Enzalutamide resistance by enhancing AR/ARv7 protein stability via reduced ubiquitination, mediated through the recruitment of the deubiquitinating enzyme USP48. These findings establish VAV2, identified through eccDNA sequencing, as a potential oncogene and a promising biomarker for PCa diagnosis and prognosis.

The androgen-dependent or -independent pathways are regarded as primary therapeutic targets for the neoplasm of the prostate. Mucosa-associated lymphoid tissue 1 (MALT1) acting as a paracaspase in the regulation of nuclear factor κB (NF-κB) signal transduction plays a central role in inflammation and oncogenesis in cancers. This study confirmed the potential linkages between androgen and NF-κB activation by inducing MALT1 in the androgen receptor-full length (ARFL)-positive LNCaP and 22Rv1 prostate cancer cells. Although androgen did not stimulate MALT1 expression in AR-null or ectopic ARFL-overexpressed PC-3 cells, the ectopic overexpression of the AR splicing variant 7 (ARv7) upregulated MALT1 to activate NF-κB activities in 22Rv1 and PC-3 cells. Since the nuclear translocation of p50 and p65 was facilitated by ARv7 to motivate NF-κB activity, the expressions of MALT1, prostate-specific antigen (PSA), and N-myc downstream regulated 1 (NDRG1) were therefore induced in ectopic ARv7-overexpressed prostate cancer cells. Ectopic ARv7 overexpression not only enhanced 22Rv1 or PC-3 cell growth and invasion in vitro but also the tumor growth of PC-3 cells in vivo. These results indicate that an androgen receptor induces MALT1 expression androgen-dependently and -independently in ARFL- or ARv7-overexpressed prostate cancer cells, suggesting a novel ARv7/MALT1/NF-κB-signaling pathway may exist in the cells of prostate cancer.

Extracellular vesicles (EVs) offer a minimally invasive approach for cancer detection and monitoring. However, the lack of standardized methods for clinical biospecimen preparation and EV isolation limits the clinical utility of EV‐based biomarker assessments. A targeted need exists for detailed analysis of plasma EV content. Our study investigates the impact of clinical sample preparation and our ExoTIC device on the quality of plasma‐derived EVs and their RNA/protein cargo in metastatic castration‐resistant prostate cancer (mCRPC) patients. We assessed sample preparation variables: blood anti‐coagulant choice (EDTA or sodium citrate), type of plasma platelet fraction (platelet‐rich or platelet‐poor), and use of protease inhibitors. EVs were isolated via ExoTIC device, followed by EV characterization and biomarker analysis using nanoparticle tracking analysis (NTA), cryogenic electron microscopy, Western blot, and digital PCR (dPCR). We detected mCRPC‐relevant proteins (ARv7 and PSMA) in EVs from all plasma sample types with different sample preparation variables. Additionally, our findings indicate that platelet‐poor plasma (PPP) is optimal for detecting EV‐ and biologically associated mCRPC biomarker miR‐375. In this pilot study (n = 3), elevated EV miR‐375 levels in PPP samples from mCRPC patients experiencing disease progression during docetaxel treatment were associated with poor therapeutic response to docetaxel chemotherapy, which aligns with our preceding in vitro and in vivo study. Optimal biospecimen preparation for EV analysis could enhance detection accuracy and patient management, highlighting detection of plasma EV‐associated mCRPC‐specific marker proteins (ARv7 and PSMA) and microRNA miR‐375. This study investigates the influence of pre‐analytical variables on the detection of EV‐based cancer biomarkers. Pre‐identified EV‐associated biomarkers in metastatic prostate cancer (miR‐375, AR‐v7, and PSMA proteins) were detected and quantified in different plasma fractions collected with different anticoagulants from the same cancer patient. Platelet‐poor plasma (PPP) fractions were found to be the most suitable for isolating EVs with adequate protein and RNA yields and the target molecule. This supports PPP fractions in future prognostic and predictive EV‐based biomarker development.

Background: The recently developed antiandrogen, Enzalutamide (Enz), has reformed the standard of care for castration resistant prostate cancer (CRPC) patients. However, Enz-resistance inevitably emerges despite success of Enz in prolonging CRPC patients’ survival. Here we found that Enz-resistant prostate cancer (PCa) cells had higher BCL2 expression. We aimed to test whether targeting BCL2 would influence Enz sensitivity of prostate cancer (PCa) and identify the potential mechanism. Methods: The study was designed to target Enz-induced BCL2 with inhibitor ABT263 and test Enz sensitivity in Enz-resistant PCa cells by MTT assay. Cellular reactive oxygen species (ROS) levels were detected with dihydroethidium staining, and in vitro deubiquitinating enzyme activity assay was used to evaluate ubiquitin specific protease 26 (USP26) activity. Results: ABT263 could increase Enz sensitivity in both Enz-sensitive and Enz-resistant PCa cells via inducing ROS generation. Elevated cellular ROS levels might then inhibit USP26 activity to increase the ubiquitination of androgen receptor (AR) and AR splice variant 7 (ARv7) and their ubiquitin/proteasome-dependent degradation, which contributed to the increase of Enz sensitivity. In vivo mouse model also demonstrates that ABT263 will suppress the PCa progression. Conclusion: This study demonstrated that targeting Enz-induced BCL2 with inhibitor ABT263 could increase Enz sensitivity in both Enz-sensitive and Enz-resistant PCa cells through induction of cellular ROS levels and suppression of USP26 activity with a consequent increase of ubiquitin/proteasome-dependent degradation of AR and ARv7 protein expression.

Background: Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) develop visceral metastases, which are associated with a poor prognosis. Objectives: Efficacy of enzalutamide in mCRPC patients with measurable metastases, including visceral and/or extra-regional lymph nodes. Methods: In this phase II multicenter study, patients with mCRPC and measurable metastases received enzalutamide as the first line. Primary endpoint: 3-month (mo) disease control rate (DCR) defined as the proportion of patients with complete (CR) or partial response (PR) or stable disease (SD) as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoint: safety. Exploratory endpoint: the association between ARv7 splicing variants in basal circulating tumor cell (CTC)-enriched blood samples and treatment response/resistance using the AdnaTest ProstateCancerSelect kit and the AdnaTest ProstateCancer Panel AR-V7. Results: From March 2017 to January 2021, 68 patients were enrolled. One patient never started treatment. Median age: 72 years. A total of 52 patients (78%) received enzalutamide as a first line for mCRPC. The median follow-up was 32 months. At the 3-month assessment, 24 patients presented an SD, 1 patient achieved a CR, and 23 patients had a PR (3-mo-DCR of 72%). Discontinuations due to adverse events (AEs), disease-related death, or disease progression occurred in 9%, 6%, and 48% of patients. All patients reported at least one grade (G) 1–2 AE: the most common were fatigue (49%) and hypertension (33%). Six G3 AEs were reported: two hypertension, one seizure, one fatigue, one diarrhea, and one headache. Basal detection of ARv7 was significantly associated with poor treatment response (p = 0.034) and a nonsignificant association (p = 0.15) was observed between ARv7 detection and response assessments. At month 3, ARv7 was detected in 57%, 25%, and 15% of patients undergoing progressive disease, SD, and PR, respectively. Conclusion: The study met its primary endpoint, showing the efficacy of enzalutamide in men with mCRPC and measurable metastatic lesions in visceral and/or lymph node sites. Trial registration: ClinicalTrials.gov Identifier: NCT03103724. First Posted: 6 April 2017. First patient enrollment: 19 April 2017.

Despite several treatment options and an initial high response rate to androgen deprivation therapy, the majority of prostate cancers will eventually become castration-resistant in the metastatic stage (mCRPC). Androgen receptor splice variant 7 (ARV7) is one of the best-characterized androgen receptor (AR) variants whose expression in circulating tumor cells (CTCs) has been associated with enzalutamide resistance. ARV7 expression analysis before and during enzalutamide treatment could identify patients requiring alternative systemic therapies. However, a robust test for the assessment of the ARV7 status in patient samples is still missing. Here, we implemented an RT-qPCR-based assay for detection of AR full length (ARFL)/ARV7 expression in CTCs for clinical use. Additionally, as a proof-of-principle, we validated a cohort of 95 mCRPC patients initiating first line treatment with enzalutamide or enzalutamide/metformin within a clinical trial. A total of 95 mCRPC patients were analyzed at baseline of whom 27.3% (26/95) had ARFL+ARV7+, 23.1% (22/95) had ARFL+ARV7−, 23.1% (22/95) had ARFL−ARV7−, and 1.1% (1/95) had ARFL−ARV7+ CTCs. In 11.6% (11/95), no CTCs could be isolated. A total of 25/95 patients had another CTC analysis at progressive disease, of whom 48% (12/25) were ARV7+. Of those, 50% (6/12) were ARV7− and 50% (6/12) were ARV7+ at baseline. Our results show that mRNA analysis of isolated CTCs in mCRPC is feasible and allows for longitudinal endocrine agent response monitoring and hence could contribute to treatment optimization in mCRPC.