18F-DCFPyL (targeted PSMA) and 18F-FDG dual-tracer PET/CT combination with next-generation sequencing was applied in a prospective cohort of men with prostate cancer to identify the clinical and genetic characteristics with heterogeneous PET/CT imaging features.

104 men with documented prostate cancer underwent 18F-DCFPyL and 18F-FDG PET/CT, of which 83 underwent next-generation sequencing for detecting variation of AR, TP53, RB1, PTEN, etc. Lesions were classified into DCFPyL+FDG± lesions and DCFPyL-FDG+ lesions and analyzed for heterogeneous distribution. We divided the patients with positive lesions into DCFPyL+FDG± group and DCFPyL-FDG+ group, then compared the differences in clinical features and genetic mutations between the two groups with CRPC.

Overall, 92 men had positive lesions detected. By comparing lesion distribution with the DCFPyL+FDG ± , DCFPyL-FDG+ disease had higher proportions of visceral metastases (4.1% vs. 1.0%, p = 0.002). DCFPyL-FDG+ was more frequently found in CRPC cohorts, and in the CRPC cohort, patients with DCFPyL-FDG+ lesions often had worse PSA response. Exploratory analysis showed that TP53 and/or RB1 mutations might be a risk factor for DCFPyL-FDG+ disease (OR = 10.625, 95% CI 3.492-32.332, p < 0.001).

Patients with DCFPyL-FDG+ lesions were more likely to have visceral metastases detected, be found in castration-resistant cohorts, have TP53 and/or RB1 mutations detected, and have poor therapeutic response compared to patients with DCFPyL+FDG± lesions. Therefore, dual-tracer (18F-DCFPyL and 18F-FDG) PET/CT is recommended for patients with low PSMA expression incompatible with the true burden of the disease and those with TP53 and/or RB1 mutations to better evaluate the disease burden, tumor heterogeneity, and prognosis.

Triterpenoids from plants are essential sources of nutraceuticals, which possess numerous positive effects on human health. Lupeol (a pentacyclic dietary triterpenoid) is commonly present in edible fruits, vegetables, and medicinal plants. Numerous investigations on the pharmacological properties of lupeol have been carried out in the past 10 years, and the results have shown that the compound has enormous pharmacological properties, including antioxidant, anti-inflammatory, and anticancer properties. Research has shown that lupeol affects the functioning of numerous molecules, including the cytokines IL-2, NFκB, IL4, IL5, cFLIP, ILβ, and Bcl-2. Our review discusses recent advancements in plant lupeol and its underlying mode of action in combating human carcinoma within the timeframe spanning from 2010 to 2024. Also, we have tried to incorporate recent studies reported till date of the finalization of this review. In order to give researchers the most recent information, highlight the limitations of pertinent research at this time, and highlight both the mechanisms of action of lupeol and recent advances in its formulations that should be strengthened in future studies.

Jaboticaba peel extract (JPE) has demonstrated chemopreventive effects on the development of prostatic lesions in experimental systems, including the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP). However, its influence over castration-resistant prostate cancer (CRPC) and the androgenic dependence of its actions in this model remain unknown. Therefore, we aimed to evaluate JPE effects on TRAMP mice tumorigenesis under different androgen reliance settings. Mice were submitted to short- or long-term JPE administration, associated or not with androgen deprivation therapy (ADT) by surgical and chemical castration. Prostate, periaortic lymph nodes and lung samples were harvested to determine the incidence of primary and metastatic lesions. Protein expression of proliferative, hormonal and angiogenesis markers was evaluated. Results showed that JPE administration in a hormone naive setting restricted poorly-differentiated tumors to the ventral prostate. Additionally, treatment extension improved the proportion of tumor-free individuals and the timeline for the development of palpable tumors. These results were paralleled by significant increment on VE-Cadherin expression. Furthermore, JPE-treated groups demonstrated significantly lower incidences of lymphatic metastasis. Conversely, JPE plus ADT resulted in poor outcomes, especially upon the extension of this association. In this setting, decreased survival, lower tumor-free mice proportion and increment of proliferative epithelial areas were registered. Altogether, such effects were attributed to a time-dependent up- (VEGF, latent TGF-β2 and TGFβ-RI) or downregulation (VEGFR-2 and VE-Cadherin) of angiogenic mediators expression. Therefore, we conclude that long-term ADT in TRAMP mice drives the prostatic microenvironment dynamics towards a proangiogenic state, which negatively impacts or even abolishes the otherwise beneficial effects of JPE.

Immunotherapy has limited effectiveness in prostate cancer (PCa), often classified as a "cold tumor" due to immune-related long non-coding RNAs (lncRNAs) and mRNAs. We developed and validated a consensus immune-related lncRNA and mRNA signature (ILMS) to enhance immunotherapy efficacy for PCa patients. By analyzing seven independent datasets, including our own, we confirmed that ILMS is a robust predictor of biochemical recurrence (BCR). Compared to 70 other published signatures, ILMS showed the highest ability to anticipate PCa prognosis. Single-cell analysis indicated that ILMS-high patients had abundant immune cell infiltration, suggesting a favorable response to immunotherapy. Additionally, ILMS was positively associated with immune checkpoints LAG3, TIM3, and TIGIT, identifying patients likely to benefit from immunotherapy. This model will be further validated and refined in subsequent studies.

Castration-resistant prostate cancer (CRPC) has been a major cause of tumor-associated death among men worldwide. The discovery of novel therapeutic medicines for CRPC remains imperative. Atractylenolide I (ATR-I), a prominent bioactive component from Atractylodes macrocephala, exhibits powerful anticancer potentials in various malignancies. Nevertheless, the ATR-I's activity on CRPC has not been reported.

An enzalutamide-resistant (EnzR) cell line was successfully constructed. CCK-8, EdU, wound healing, Transwell assays, flow cytometry, and xenograft tumor models were applied to investigate the antitumor activity of ATR-I against CRPC. The changes in the gene expression profiles after ATR-I treatment were analyzed using RNA sequencing.

ATR-I suppressed the proliferative and migratory abilities of AR+ and AR- CRPC cells, while triggering cell cycle arrest and apoptosis. ATR-I also exerted anti-cancer activity on EnzR cell lines. Intriguingly, a combination of ATR-I with enzalutamide synergistically induced more apoptosis of tumor cells. RNA-sequencing identified kinesin family member 15 (KIF15) as a potential target of ATR-I. KIF15 was up-regulated in prostate cancer (PCa), and its higher level was associated with poorer clinical outcomes. Further investigation showed that ATR-I mediated ubiquitin-proteasomal degradation of AR/AR-V7 through targeting KIF15, resulting in CRPC repression. Finally, our in vivo experiment verified that ATR-I alone or in combination with enzalutamide retarded the growth of EnzR xenograft tumors.

These findings identified ATR-I as a promising therapeutic drug for overcoming enzalutamide resistance in CRPC patients and increased our understanding about its antitumor mechanisms.

The transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) plays a role in carcinogenesis and is involved in processes, such as proliferation, differentiation, drug resistance and immunosuppression. STAT3 can be activated by phosphorylation of tyrosine at position 705 (pSTAT3Tyr705) or serine at 727 (pSTAT3Ser727). High expression levels of pSTAT3 are implicated in advanced stages of prostate cancer (PCa) and are known to interact with the androgen receptor signaling pathway. However, not much is known about how androgen deprivation therapy (ADT) in advanced disease affects pSTAT3 expression. The aim of this study was to determine the influence of ADT on pSTAT3 expression in PCa tissue.

The study cohort came from a PCa tissue microarray resource containing prostate specimens from patients before and post-initiation of ADT. Tissue samples from 111 patients were immunostained for pSTAT3Tyr705 and pSTAT3Ser727. H-score was used to evaluate the intensity and the percentage of pSTAT3 expression in malignant epithelial and stromal compartments. Univariate and multivariable Cox regression analyses were used to assess pSTAT3Tyr705 and pSTAT3Ser727 as biomarkers of oncological outcome in patients undergoing ADT.

Post-ADT PCa samples demonstrated increased nuclear and cytoplasmic levels of pSTAT3Ser727 in the stroma compared to pre-ADT samples, whereas pSTAT3Tyr705 expression was increased significantly in both stromal and malignant epithelial compartments except for stromal cytoplasm. High cytoplasmic pSTAT3Ser727 in stromal compartments correlated with reduced overall survival, shorter time to castration-resistant PCa development, and decreased metastasis-free survival. An increase in nuclear and cytoplasmic pSTAT3Ser727 expression within the stromal compartment of post-ADT samples corresponded to a shorter time to CRPC development, which was not observed for pSTAT3Tyr705. Multivariable survival analysis using Cox's regression identified that high cytoplasmic pSTAT3Ser727 expression in the stroma of post-ADT samples and pT3 or pT4-stage were associated with worse overall survival and 5-year metastasis-free survival (MFS).

This study presents novel insights into the impact of ADT on the expression levels of pSTAT3Tyr705 and pSTAT3Ser727 in PCa. Cytoplasmic pSTAT3Ser727 status of cancer-associated stromal cells in post-ADT samples may serve as an independent prognostic marker for OS and 5-year MFS, identifying prostate cancer patients prone to developing resistance to ADT.

Drug resistance is an important factor for prostate cancer (PCa) to progress into refractory PCa, and abnormal lipid metabolism usually occurs in refractory PCa, which presents great challenges for PCa therapy. Here, a cluster of differentiation 36 (CD36) inhibitor sulfosuccinimidyl oleate sodium (CD36i) and stearoyl-CoA desaturase 1 (SCD1) siRNA (siSCD1) are selected to inhibit lipid uptake and synthesis in PCa, respectively. To this end, a multiresponsive drug delivery nanosystem, HA@CD36i-TR@siSCD1 is designed. The hyaluronic acid (HA) gel "shell" of HA-TR nanosystem can release drugs in response to the acidic tumor microenvironment and hyaluronidase, and the tumor targeting (TR) cationic micellar "core" can release drugs in response to glutathione. This multiresponsive drug release is beneficial for the exogenous inhibition of lipid uptake by CD36i and the endogenous inhibition of lipid synthesis by siSCD1. The established HA-TR nanosystem has good tumor targeting ability and tumor penetration ability, and that HA@CD36i-TR@siSCD1 has good synergistic effects, which can significantly restrain the growth, invasion, and metastasis of PCa. Moreover, under high-fat conditions, the tumors are more sensitive to HA@CD36i-TR@siSCD1 treatment, almost no accumulation of lipid droplets is observed in HA@CD36i-TR@siSCD1-treated tumors, with enhanced antitumor immunity. Hence, this study provides a new treatment option for refractory PCa patients, especially those with a high-fat diet.

Androgen deprivation is the standard treatment for patients with prostate cancer. However, the disease eventually progresses as castration-resistant prostate cancer (CRPC). Enzalutamide, an androgen receptor inhibitor, is a typical drug for treating CRPC and with continuous reliance on the drug, can lead to enzalutamide resistance. This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential antitumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of enzalutamide-resistant CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in enzalutamide-resistant CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro. Following these results, we sought to explore how combination treatment affected mitochondrial fitness using mitochondrial stress test analysis and mitochondrial membrane potential shifts due to metformin's action in inhibiting complex I of oxidative phosphorylation. We employed 2 different strategies for in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of rat sarcoma-mitogen-activated protein kinase signaling following combination treatment. SIGNIFICANCE STATEMENT: Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. This study showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.

The Androgen Receptor (AR) pathway is crucial in driving the progression of prostate cancer (PCa) to an advanced state. Despite the introduction of second-generation AR antagonists, such as enzalutamide, majority of patients develop resistance. Several mechanisms of resistance have been identified, including the constitutive activation of the AR pathway, the emergence of AR spliced variants, and the influence of other signalling pathways. The Serum Response Factor (SRF) was previously identified as a possible player of resistance involved in a crosstalk with the AR signalling pathway. Elevated SRF levels in PCa patients were associated with disease progression and resistance to enzalutamide. However, the molecular mediators of the crosstalk between SRF and AR still need to be elucidated. The objective of this study was to identify common interactors of the AR/SRF crosstalk as therapeutic targets.

Here we used affinity purification mass spectrometry (MS) following immunoprecipitation of SRF and AR, to identify proteins that interact with both SRF and AR. The list of common interactors was expanded using STRING. Four common interactors were functionally validated using MTT assays.

Seven common interactors were identified, including HSP70, HSP0AA1, HSP90AB1, HSAP5, PRDX1 and GAPDH. Pathway analysis revealed that the PI3k/AKT pathway was the most enriched in the AR/SRF network. Moreover, pharmacological inhibition of several proteins in this network, including HSP70, HSP90, PI3k and AKT, significantly decreased cellular viability of PCa cells.

This study identified a list of AR/SRF common interactors that represent a pipeline of druggable targets for the treatment of PCa.

Prostate cancer (PCa) is an androgen-dependent disease, with castration-resistant prostate cancer (CRPC) being an advanced stage that no longer responds to androgen deprivation therapy (ADT). Mounting evidence suggests that glucocorticoid receptors (GR) confer resistance to ADT in CRPC patients by bypassing androgen receptor (AR) blockade. GR, as a novel therapeutic target in CRPC, has attracted substantial attention worldwide. This study utilized bioinformatic analysis of publicly available CRPC single-cell data to develop a consensus glucocorticoid-related signature (Glu-sig) that can serve as an independent predictor for relapse-free survival. Our results revealed that the signature demonstrated consistent and robust performance across seven publicly accessible datasets and an internal cohort. Furthermore, our findings demonstrated that glycerol-3-phosphate dehydrogenase 1 (GPD1) in Glu-sig can significantly promote CRPC progression by mediating the cell cycle pathway. Additionally, GPD1 was shown to be regulated by GR, with the GR antagonist mifepristone enhancing the anti-tumorigenic effects of GPD1 in CRPC cells. Mechanistically, targeting GPD1 induced the production of sphingosine 1-phosphate (S1P) and enhanced histone acetylation, thereby inducing the transcription of p21 that involved in cell cycle regulation. In conclusion, Glu-sig could serve as a robust and promising tool to improve the clinical outcomes of PCa patients, and modulating the GR/GPD1 axis that promotes tumor growth may be a promising approach for delaying CRPC progression.

Aims: Dopamine agonists (DAs) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between androgen receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance. Results: Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to bromocriptine (BRC) both in vitro and in vivo. Mechanistically, we demonstrated that intracellular reactive oxygen species (ROS) function as upstream mediators of apoptosis and ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NFE2-like bZIP transcription factor 2 (NRF2) expression, which regulates intracellular ROS levels, thereby enhancing cell viability and conferring DA resistance to pituitary adenoma (PA) cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment. Conclusion and Innovation: We demonstrated that AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas. Antioxid. Redox Signal. 00, 000-000.

Although targeting the androgen signaling pathway by androgen receptor (AR) inhibitors, including enzalutamide, has shown therapeutic effectiveness, inevitable emergence of acquired resistance remains a critical challenge in the treatment of advanced prostate cancer (PCa). Recognizing targetable genomic aberrations that trigger endocrine treatment failure holds great promise for advancing therapeutic interventions. Here, we characterized PLXNA1, amplified in a subset of PCa patients, as a contributor to enzalutamide resistance (ENZR). Elevated PLXNA1 expression facilitated PCa proliferation under enzalutamide treatment due to AKT signaling activation. Mechanistically, PLXNA1 recruited NRP1 forming a PLXNA1-NRP1 complex, which in turn potentiated the phosphorylation of the AKT. Either inhibiting PLXNA1-NRP1 complex with an NRP1 inhibitor, EG01377, or targeting PLXNA1-mediated ENZR with AKT inhibitors, abolished the pro-resistance phenotype of PLXNA1. Taken together, combination of AKT inhibitor and AR inhibitors presents a promising therapeutic strategy for PCa, especially in advanced PCa patients exhibiting PLXNA1 overexpression.

Enzalutamide (Enz) resistance is a poor prognostic factor for patients with castration-resistant prostate cancer (CRPC), which often involves aberrant expression of the androgen receptor (AR). Myosin VI (MYO6), one member of the myosin family, plays an important role in regulating cell survival and is highly expressed in prostate cancer (PCa). However, whether MYO6 is involved in Enz resistance in CRPC and its mechanism remain unclear.

Multiple open-access databases were utilized to examine the relationship between MYO6 expression and PCa progression, and to screen differentially expressed genes (DEGs) and potential signaling pathways associated with the MYO6-regulated Enz resistance. Both in vitro and in vivo tumorigenesis assays were employed to examine the impact of MYO6 on the growth and Enz resistance of PCa cells. Human PCa tissues and related clinical biochemical data were utilized to identify the role of MYO6 in promoting PCa progression and Enz resistance. The molecular mechanisms underlying the regulation of gene expression, PCa progression, and Enz resistance in CRPC by MYO6 were investigated.

MYO6 expression increases in patients with PCa and is positively correlated with AR expression in PCa cell lines and tissues. Overexpression of AR increases MYO6 expression to promote PCa cell proliferation, migration and invasion, and to inhibit PCa cell apoptosis; whereas knockdown of MYO6 expression reverses these outcomes and enhances Enz function in suppressing the proliferation of the Enz- sensitive and resistant PCa cells both in vitro and in vivo. Mechanistically, AR binds directly to the promoter region (residues - 503 to - 283 base pairs) of MYO6 gene and promotes its transcription. Furthermore, MYO6 activates focal adhesion kinase (FAK) phosphorylation at tyrosine-397 through integrin beta 8 (ITGB8) modulation to promote PCa progression and Enz resistance. Notably, inhibition of FAK activity by Y15, an inhibitor of FAK, can resensitize CRPC cells to Enz treatment in cell lines and mouse xenograft models.

MYO6 has pro-tumor and Enz-resistant effects in CRPC, suggesting that targeting MYO6 may be beneficial for ENZ-resistant CRPC therapy through the AR/MYO6/FAK signaling pathway.

MicroRNAs are a conserved class of small, tissue-specific, non-coding RNAs that regulate gene expression to preserve cellular homeostasis. Proper miRNA expression is crucial for physiological balance because it affects numerous genetic pathways, including cell cycle control, proliferation, and apoptosis, through gene expression targeting. Deregulated miRNA expression has been implicated in several cancer types, including prostate cancer (PC), acting as tumor suppressors or oncogenes. Despite the availability of promising therapies to control tumor growth and progression, effective diagnostic and therapeutic strategies for different types of cancer are still lacking. PC continues to be a significant health challenge, particularly its castration-resistant (CRPC) form, which presents major therapeutic obstacles because of its resistance to conventional androgen deprivation treatments. This review explores miRNAs' critical roles in gene regulation and cancer biology, as well as various miRNA delivery systems, highlighting their potential and the challenges in effectively targeting cancer cells. It aims to provide a comprehensive overview of the status of miRNA research in the fight against CRPC, summarizing miRNA-based therapies' successes and limitations. It also highlights the promise of miRNAs as therapeutic agents for CRPC, underlining the need for further research to overcome existing challenges and move these therapies toward clinical applications.

Deutenzalutamide is a new molecular entity androgen receptor antagonist. The primary aim of this study was to develop a population pharmacokinetic model of deutenzalutamide and evaluate effects of intrinsic and extrinsic factors on pharmacokinetics. A nonlinear mixed-effects modeling approach was performed to develop the population pharmacokinetic of deutenzalutamide using data from 1 Phase I trial of deutenzalutamide. Goodness-of-fit plots, prediction-corrected visual predictive check, and bootstrap analysis were carried out to evaluate the final model. Simulation for the developed model was used to evaluate the covariate effects on the pharmacokinetics of deutenzalutamide. A 2-compartment model with first-order absorption and elimination from the central compartment was established for deutenzalutamide. The final covariate included body weight on peripheral compartment volume. This is the first research developing the population pharmacokinetic model of deutenzalutamide in patients with metastatic castration-resistant prostate cancer, and it is expected to support the future clinical administration of deutenzalutamide.

Prostate cancer development and progression are driven by androgens, and changes in androgen metabolic pathways can lead to prostate cancer progression or remission. AKR1C2 is a member of the aldo-keto reductase superfamily and plays an important role in the metabolism of steroids and prostaglandins. Alterations in the expression and activity of AKR1C2 affect the homeostasis of active androgens, which in turn affects the progression of prostate cancer. AKR1C2 reduces the highly active dihydrotestosterone to the less active 3α-diol in the prostate, resulting in lower androgen levels. Whereas the expression of AKR1C2 is significantly reduced in prostate cancer tissues relative to normal prostate tissues, this results in a weakening of the dihydrotestosterone metabolic inactivation pathway, leading to the retention of dihydrotestosterone in the prostate cancer cells, which promotes the progress of prostate cancer. Given the critical role of AKR1C2 in prostate cancer cells, targeting AKR1C2 for the treatment of prostate cancer may be an effective strategy. It has been demonstrated that curcumin and neem leaf extract effectively inhibit prostate cancer in vitro and in vivo by modulating AKR1C2.

Prostate cancer (PC) depicts a major health challenge all over the globe due to its complexities in the treatment and diverse clinical trajectories. Even in the advances in the modern treatment strategies, the spectrum of resistance to the therapies continues to be a significant challenge. This review comprehensively examines the underlying mechanisms of the therapy resistance occurred in PC, focusing on both the tumor microenvironment and the signaling pathways implicated in the resistance. Tumor microenvironment comprises of stromal and epithelial cells, which influences tumor growth, response to therapy and progression. Mechanisms such as microenvironmental epithelial-mesenchymal transition (EMT), anoikis suppression and stimulation of angiogenesis results in therapy resistance. Moreover, dysregulation of signaling pathways including androgen receptor (AR), mammalian target of rapamycin/phosphoinositide 3 kinase/AKT (mTOR/PI3K/AKT), DNA damage repair and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways drive therapy resistance by promoting tumor survival and proliferation. Understanding these molecular pathways is important for developing targeted therapeutic interventions which overcomes resistance. In conclusion, a complete grasp of mechanisms and pathways underlying medication resistance in PC is important for the development of individualized treatment plans and enhancements of clinical outcomes. By studying and understanding the complex mechanisms of signaling pathways and microenvironmental factors contributing to therapy resistance, this study focuses and aims to guide the development of innovative therapeutic approaches to effectively overcome the PC progression and improve the survival rate of patients.

Prostate cancer progression is driven by androgen receptor (AR) activity, which is a target for therapeutic approaches. Enzalutamide is an AR inhibitor that prolongs the survival of patients with advanced prostate cancer. However, resistance mechanisms arise and impair its efficacy. One of these mechanisms is the expression of AR-V7, a constitutively active AR splice variant. The Mediator complex is a multisubunit protein that modulates gene expression on a genome-wide scale. MED12 and cyclin-dependent kinase (CDK)8, or its paralog CDK19, are components of the kinase module that regulates the proliferation of prostate cancer cells. In this study, we investigated how MED12 and CDK8/19 influence cancer-driven processes in prostate cancer cell lines, focusing on AR activity and the enzalutamide response. We inhibited MED12 expression and CDK8/19 activity in LNCaP (AR+, enzalutamide-sensitive), 22Rv1 (AR-V7+, enzalutamide-resistant), and PC3 (AR-, enzalutamide-insensitive) cells. Both MED12 and CDK8/19 inhibition reduced cell proliferation in all cell lines, and MED12 inhibition reduced proliferation in the respective 3D spheroids. MED12 knockdown significantly inhibited c-Myc protein expression and signaling pathways. In 22Rv1 cells, it consistently inhibited the AR response, prostate-specific antigen (PSA) secretion, AR target genes, and AR-V7 expression. Combined with enzalutamide, MED12 inhibition additively decreased the AR activity in both LNCaP and 22Rv1 cells. CDK8/19 inhibition significantly decreased PSA secretion in LNCaP and 22Rv1 cells and, when combined with enzalutamide, additively reduced proliferation in 22Rv1 cells. Our study revealed that MED12 and CDK8/19 regulate AR activity and that their inhibition may modulate response to enzalutamide in prostate cancer.

Prostate cancer is a lethal solid malignancy and a leading cause of cancer-related deaths in males worldwide. Treatments, including radical prostatectomy, radiotherapy, and hormone therapy, are available and have improved patient survival; however, recurrence remains a huge clinical challenge. Enzalutamide is a second-generation androgen receptor antagonist that is used to treat castrate-resistant prostate cancer. Among patients who initially respond to enzalutamide, virtually all acquire secondary resistance, and an improved understanding of the mechanisms involved is urgently needed. Aberrant glycosylation, and, in particular, alterations to sialylated glycans, have been reported as mediators of therapy resistance in cancer, but a link between tumour-associated glycans and resistance to therapy in prostate cancer has not yet been investigated. Here, using cell line models, we show that prostate cancer cells with acquired resistance to enzalutamide therapy have an upregulation of the sialyltransferase ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) and increased levels of α2,6-sialylated N-glycans. Furthermore, using the sialyltransferase inhibitor P-SiaFNEtoc, we discover that acquired resistance to enzalutamide can be partially reversed by combining enzalutamide therapy with sialic acid blockade. Our findings identify a potential role for ST6GAL1-mediated aberrant sialylation in acquired resistance to enzalutamide therapy for prostate cancer and suggest that sialic acid blockade in combination with enzalutamide may represent a novel therapeutic approach in patients with advanced disease. Our study also highlights the potential to bridge the fields of cancer biology and glycobiology to develop novel combination therapies for prostate cancer.

Sharply increased reactive oxygen species (ROS) are thought to induce oxidative stress, damage cell structure and cause cell death; however, its role in prostate cancer remains unclear. Enzalutamide is a widely used anti-prostate cancer drug that antagonizes androgen binding with its receptor. Further exploration of the mechanism and potential application strategies of enzalutamide is crucial for the treatment of prostate cancer. Here, we confirmed PEX10 can be induced by ROS activators while reduce ROS level in prostate cancer cells, which weakened the anti-tumor effect of ROS activators. The androgen receptor (AR) can promote the expression of PEX10 by acting as an enhancer in cooperation with FOXA1. The anti-tumor drug enzalutamide inhibits PEX10 by inhibiting the function of AR, and synergize with ROS activators ML210 or RSL3 to produce a stronger anti-tumor effect, thereby sensitizing cells to ROS activators. This study reveals a previously unrecognized function of enzalutamide and AR by regulating PEX10 and suggests a new strategy of enzalutamide application in prostate cancer treatment.

Despite the initial efficacy of enzalutamide in castration-resistant prostate cancer (CRPC), inevitable resistance remains a significant challenge. Here, the synergistic induction of copper-dependent cell death (cuproptosis) in CRPC cells is reported by enzalutamide and copper ionophores (elesclomol/disulfiram). Mechanistically, enzalutamide treatment increases mitochondrial dependence in CRPC cells, rendering them susceptible to cuproptosis, as evidenced by specific reversal with the copper chelator tetrathiomolybdate. This susceptibility is characterized by hallmarks of cuproptosis, including lipoylated protein aggregation and iron-sulfur cluster protein instability. Interestingly, the mitochondrial matrix reductase, FDX1, specifically correlates with elesclomol sensitivity, suggesting a potential mechanistic divergence between the two copper ionophores. Notably, this synergistic effect extends beyond in vitro models, demonstrating efficacy in 22Rv1 xenografts, mouse Pten p53 knockout organoids. Importantly, enzalutamide significantly enhances copper ionophore-mediated cytotoxicity in enzalutamide-resistant cells. Collectively, these findings indicate that enzalutamide and copper ionophores synergistically induce cuproptosis, offering a promising therapeutic avenue for CRPC, potentially including enzalutamide-resistant cases.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 was highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression was associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibited neural lineage pathways, thereby suppressing NEPC cell proliferation, patient derived xenograft (PDX) tumor organoid viability, and xenograft tumor growth. Mechanistically, the heat shock protein 70 (HSP70) regulated PLXND1 protein stability through degradation, and inhibition of HSP70 decreased PLXND1 expression and NEPC organoid growth. In summary, our findings indicate that PLXND1 could serve as a promising therapeutic target and molecular marker for NEPC.

Background: Castration-resistant prostate cancer (CRPC), which has developed resistance to next-generation antiandrogens, such as enzalutamide (Enz), is a lethal disease. Furthermore, transcriptional regulation by super enhancers (SEs) is crucial for the growth and spread of prostate cancer, as well as drug resistance. The functions of SEs, a significant class of noncoding DNA cis-regulatory elements, have been the subject of numerous recent studies in the field of cancer research. Materials and Methods: The goal of this research was to identify SEs associated with Enz resistance in C4-2B cells using chromatin immunoprecipitation sequencing and cleavage under targets and tagmentation (CUT&Tag). Using HOMER analysis to predict protein/gene-binding motifs, we identified master transcription factors (TFs) that may bind to SE sites. Using small interfering RNA, WST-1 assays, and qRT-PCR, we then confirmed the associations between TFs of SEs and Enz resistance. Results: A total of 999 SEs were screened from C4-2B EnzR cells in total. Incorporating analysis with RNA-seq data revealed 41 SEs to be strongly associated with the promotion of Enz resistance. In addition, we finally predicted that master TFs bind to SE-binding regions. Subsequently, we selected zinc finger protein 467 (ZFP467) and SMAD family member 3 to confirm the functional connections of master TFs with Enz resistance through SEs (ZNF467). Conclusions: In this study, SMAD3 and ZNF467 were found to be closely related to Enz-resistant CRPC. Our research uncovered a sizable group of SEs linked to Enz resistance in prostate cancer, dissected the mechanisms underlying SE Enz resistance, and shed light on potential clinical uses for SEs.

Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer deaths among American men. Androgen deprivation therapy (ADT) has been systemically applied as a first-line therapy for PCa patients. Despite the initial responses, the majority of patients under ADT eventually experienced tumor progression to castration-resistant prostate cancer (CRPC), further leading to tumor metastasis to distant organs. Therefore, identifying the key molecular mechanisms underlying PCa progression remains crucial for the development of novel therapies for metastatic PCa. Previously, we identified that tumor-suppressive miR-99b-5p is frequently downregulated in aggressive African American (AA) PCa and European American (EA) CRPC, leading to upregulation of mTOR, androgen receptor (AR), and HIF-1α signaling. Given the fact that mTOR and HIF-1α signaling are critical upstream pathways that trigger the activation of epithelial-mesenchymal transition (EMT), we hypothesized that miR-99b-5p may play a critical functional role in regulating EMT-mediated PCa metastasis. To test this hypothesis, a series of cell biology, biochemical, and in vitro functional assays (wound healing, transwell migration, cell/ECM adhesion, and capillary-like tube formation assays) were performed to examine the effects of miR-99b-5p mimic on regulating EMT-mediated PCa metastasis processes. Our results have demonstrated that miR-99b-5p simultaneously targets MTOR and AR signaling, leading to upregulation of E-cadherin, downregulation of Snail/N-cadherin/Vimentin, and suppression of EMT-mediated PCa metastasis. MiR-99b-5p alone and in combination with enzalutamide or abiraterone significantly inhibits the EMT-mediated metastasis of AA PCa and EA CRPC.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 is highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression is associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibit neural lineage pathways, suppressing NEPC cell proliferation, PDX tumor organoid viability, and xenograft tumor growth. Mechanistically, the chaperone protein HSP70 regulates PLXND1 protein stability through degradation, and inhibition of HSP70 decreases PLXND1 expression and NEPC organoid growth. In summary, our findings suggest that PLXND1 could be a new therapeutic target and molecular indicator for NEPC.

Prostate cancer (PCa) is the most prevalent solid organ malignancy and seriously affects male health. The adverse effects of prostate cancer therapeutics can cause secondary damage to patients. Nanotherapeutics, which have special targeting abilities and controlled therapeutic release profiles, may serve as alternative agents for PCa treatment. At present, many nanotherapeutics have been developed to treat PCa and have shown better treatment effects in animals than traditional therapeutics. Although PCa nanotherapeutics are highly attractive, few successful cases have been reported in clinical practice. To help researchers design valuable nanotherapeutics for PCa treatment and avoid useless efforts, herein, we first reviewed the strategies and challenges involved in prostate cancer treatment. Subsequently, we presented a comprehensive review of nanotherapeutics for PCa treatment, including their targeting methods, controlled release strategies, therapeutic approaches and mechanisms. Finally, we proposed the future prospects of nanotherapeutics for PCa treatment.

Androgen receptors (ARs) play key roles in prostate cancer (PCa) progression and castration-resistant prostate cancer (CRPC) resistance to drug therapy. SET and MYND domain containing protein 2 (SMYD2), a lysine methyltransferase, has been reported to promote tumors by transcriptionally methylating important oncogenes or tumor repressor genes. However, the role of SMYD2 in CRPC drug resistance remains unclear. In this study, we found that SMYD2 expression was significantly upregulated in PCa tissues and cell lines. High SMYD2 expression indicated poor CRPC-free survival and overall survival in patients. SMYD2 knockdown dramatically inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) potential of 22Rv1 and C4-2 cells. Conversely, ectopic overexpression of SMYD2 promoted these effects in 22Rv1 and C4-2 cells. Mechanistically, SMYD2 methylated and phosphorylated ARs to affect AR ubiquitination and proteasome degradation, which further alters the AR transcriptome in CRPC cells. Importantly, the SMYD2 inhibitor AZ505 had a synergistic therapeutic effect with enzalutamide in CRPC cells and mouse models; however, it could also re-sensitize resistant CRPC cells to enzalutamide. Our findings demonstrated that SMYD2 enhances the methylation and phosphorylation of ARs and affects AR ubiquitination and proteasome degradation to modulate CRPC cell resistance to enzalutamide, indicating that SMYD2 serves as a crucial oncogene in PCa and is an ideal therapeutic target for CRPC.

Prostate cancer (PC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related deaths in male population worldwide. Since the growth and progression of PC highly depend on the androgen pathway, androgen deprivation therapy (ADT) is the mainstay of systemic treatment. Enzalutamide is a second-generation antiandrogen, which is widely used for the treatment of advanced and metastatic PC. However, treatment failure and disease progression, caused by the emergence of enzalutamide resistant phenotypes, remains an important clinical challenge. MicroRNAs (miRNAs) are key regulators of gene expression and have recently emerged as potential biomarkers for being stable and easily analysed in several biological fluids. Several miRNAs that exhibit dysregulated expression patterns in enzalutamide-resistant PC have recently been identified, including miRNAs that modulate critical signalling pathways and genes involved in PC growth, survival and in the acquisition of enzalutamide phenotype. The understanding of molecular mechanisms by which miRNAs promote the development of enzalutamide resistance can provide valuable insights into the complex interplay between miRNAs, gene regulation, and treatment response in PC. Moreover, these miRNAs could serve as valuable tools for monitoring treatment response and disease progression during enzalutamide administration. This review summarises the miRNAs associated with enzalutamide resistance in PC already described in the literature, focusing on their biological roles and on their potential as biomarkers.

Although epithelial-mesenchymal markers play an important role in prostate cancer (PC), further research is needed to better understand their utility in diagnosis, cancer progression prevention, and treatment resistance prediction. Our study included 111 PC patients who underwent transurethral resection, as well as 16 healthy controls. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to examine the expression of E-cadherin, β-catenin, and Vimentin. We found that E-cadherin and β-catenin were underexpressed in primary PC tissues. E-cadherin expression was found to be inversely associated with prostate-specific antigen progression (PSA-P; serum marker of progression; p = 0.01; |r| = 0.262). Furthermore, the underexpression of two markers, E-cadherin and β-catenin, was found to be associated with advanced tumor stage and grade (p < 0.05). On the other hand, Vimentin was overexpressed in PC patients with a fold change of 2.141, and it was associated with the diagnosis, prognosis, and prediction of treatment resistance to androgen deprivation therapy (p = 0.002), abiraterone-acid (p = 0.001), and taxanes (p = 0.029). Moreover, the current study highlighted that poor survival could be significantly found in patients who progressed after primary surgery, did not use drugs, and expressed these genes aberrantly. In Cox regression multivariate analysis (p < 0.05), a positive correlation between the Vimentin marker and coronary heart disease in PC patients was identified (p = 0.034). In summary, the present study highlights the diagnostic (p < 0.001), prognostic (p < 0.001), and therapeutic potential of Vimentin in primary PC (p < 0.05), as well as its implications for cardiovascular disease. Furthermore, we confirm the potential prognostic value of E-cadherin and β-catenin.

The incidence of prostate cancer (PCa), the most prevalent malignancy, is currently at the forefront. RNA modification is a subfield of the booming field of epigenetics. To date, more than 170 types of RNA modifications have been described, and N6-methyladenosine (m6A) is the most abundant and well-characterized internal modification of mRNAs involved in various aspects of cancer progression. METTL3, the first identified key methyltransferase, regulates human mRNA and non-coding RNA expression in an m6A-dependent manner. This review elucidates the biological function and role of METTL3 in PCa and discusses the implications of METTL3 as a potential therapeutic target for future research directions and clinical applications.

Androgen receptor pathway inhibitors (ARPI) and polyadenosine diphosphate-ribose inhibitors (PARPi) are part of the standard of care in patients with metastatic castration-resistant prostate cancer (mCRPC). There is biological evidence that the association of ARPI and PARPi could have a synergistic effect; therefore, several ongoing clinical trials are investigating the efficacy of this combination with preliminary results that are not perfectly concordant in identifying patients who can obtain the most benefit from this therapeutic option. The purpose of this review is to describe the PARPi mechanisms of action and to analyze the biological mechanisms behind the interplay between the androgen receptor and the PARPi system to better understand the rationale of the ARPI + PARPi combinations. Furthermore, we will summarize the preliminary results of the ongoing studies on these combinations, trying to understand in which patients to apply. Finally, we will discuss the clinical implications of this combination and its possible future perspectives.

Prostate cancer (PCa) is the second most common and fifth most aggressive neoplasm among men worldwide. In the last decade, extracellular vesicle (EV) research has decoded multiple unsolved cancer-related mysteries. EVs can be classified as microvesicles, apoptotic bodies, and exosomes, among others. Exosomes play a key role in cellular signaling. Their internal cargos (nucleic acids, proteins, lipids) influence the recipient cell. In PCa, the exosome is the regulator of cancer progression. It is also a promising theranostics tool for PCa. Moreover, exosomes have strong participation in male fertility complications. This review aims to highlight the exosome theranostics signature in PCa and its association with male fertility.

Since the start of the 21st century, prostate cancer with lung metastasis (PCLM) has accumulated significant scientific research output. However, a systematic knowledge framework for PCLM is still lacking.

To reconstruct the global knowledge system in the field of PCLM, sort out hot research directions, and provide reference for the clinical and mechanism research of PCLM.

We retrieved 280 high-quality papers from the Web of Science Core Collection and conducted a bibliometric analysis of keywords, publication volume, and citation frequency. Additionally, we selected differentially expressed genes from global high-throughput datasets and performed enrichment analysis and protein-protein interaction analysis to further summarize and explore the mechanisms of PCLM.

PCLM has received extensive attention over the past 22 years, but there is an uneven spatial distribution in PCLM research. In the clinical aspect, the treatment of PCLM is mainly based on chemotherapy and immunotherapy, while diagnosis relies on methods such as prostate-specific membrane antigen positron emission tomography/computed tomography. In the basic research aspect, the focus is on cell adhesion molecules and signal transducer and activator of transcription 3, among others. Traditional treatments, such as chemotherapy, remain the mainstay of PCLM treatment, while novel approaches such as immunotherapy have limited effectiveness in PCLM. This study reveals for the first time that pathways related to coronavirus disease 2019, cytokine-cytokine receptor interaction, and ribosome are closely associated with PCLM.

Future research should focus on exploring and enhancing mechanisms such as cytokine-cytokine receptor interaction and ribosome and improve existing mechanisms like cadherin binding and cell adhesion molecules.

Prostate cancer (CaP) is one of the most prevalent male malignancies, accounting for a considerable number of annual mortalities. However, the prompt identification of early-stage CaP often faces delays due to diverse factors, including socioeconomic inequalities. The androgen receptor (AR), in conjunction with various other signaling pathways, exerts a central influence on the genesis, progression, and metastasis of CaP, with androgen deprivation therapy (ADT) serving as the primary therapeutic strategy. Therapeutic modalities encompassing surgery, chemotherapy, hormonal intervention, and radiotherapy have been formulated for addressing early and metastatic CaP. Nonetheless, the heterogeneous tumor microenvironment frequently triggers the activation of signaling pathways, culminating in the emergence of chemoresistance, an aspect to which cancer stem cells (CSCs) notably contribute. Phytochemicals emerge as reservoirs of bioactive agents conferring manifold advantages against human morbidity. Several of these phytochemicals demonstrate potential chemoprotective and chemosensitizing properties against CaP, with selectivity exhibited towards malignant cells while sparing their normal counterparts. In this context, the present review aims to elucidate the intricate molecular underpinnings associated with metastatic CaP development and the acquisition of chemoresistance. Moreover, the contributions of phytochemicals to ameliorating CaP initiation, progression, and chemoresistance are also discussed.