bims-meproc 2026-04-19 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–04–19
28 papers selected by
Grigor Varuzhanyan, UCLA

Role of the cross-regulation between Wnt pathway activation and androgen receptor signaling in prostate cancer treatment resistance.
Aberrant activation of epigenetic BRD9-DGAT1 axis promotes lipid droplets deposition and ferroptosis resistance in YAP-high prostate cancer.
SOX11-mediated CXCL10/CXCR3 activation promotes neuroendocrine prostate cancer.
Multi omics network toxicology and in vitro experiments elucidate the role of benzo [a] pyrene in prostate cancer.
CRIP1 promotes docetaxel resistance and immune-associated cell death modulation in prostate cancer.
Ailanthone targets the EGR3-SOCS2 regulatory pathway to suppress vasculogenic mimicry in prostate cancer.
WTAP stabilized by USP7 contributes to enzalutamide resistance in prostate cancer via mediating AKT m6A-modification.
Construction of a survival model for predicting biochemical recurrence of prostate cancer based on propionate metabolism-related genes.
Mechanistic investigation of Corydalis yanhusuo in prostate cancer: Targeting the miR-192-5p-PI3K/AKT/mTOR and STAT3-HSP90 pathways.
G Protein-Coupled Oestrogen Receptor Actions Targeting the Hallmarks of Cancer in Human Prostate Cells: From Cell Fate to Metabolic Reprogramming.
Comparison of prostate cancer diagnostic models based on PCA3 and TMPRSS2:ERG RNA biomarkers from post-DRE and non-DRE urine specimens.
α-mangostin, a xanthone from garcinia mangostana fruit inhibits MEK1 kinase in prostate cancer.
SUMOylation of EphB4 enhances its stability in prostate cancer.
Intersection of Phenotypic Plasticity and Anoikis Enhances Therapeutic Vulnerability in Prostate Cancer.
Varicocele and Untreated Hypogonadism Synergistically Increase Prostate Cancer Risk via Testosterone Shunt Physiology and can be Ameliorated with Testosterone Therapy.
Single-Cell and Spatial Transcriptomics Reveal That TXNIP and BIRC3 Contribute to Human Prostate Tumor Progression.
Protein Kinase D1 Translocates PARP1 to the Membrane and Is Associated With Increased Sensitivity to Cell Viability Inhibition by PARP1 Inhibitor Olaparib.
Identification of a Novel Trifluoromethyl-Bearing Flavonoid as a Promising Androgen Receptor Antagonist: Structure-Based Virtual Screening and In Vitro Study.
Betulinic acid induces lysosome-dependent death in prostate cancer by targeting DDX5.
Dual BRD4/AKT inhibition overcomes c-MYC-driven resistance in metastatic castration-resistant prostate cancer.
Hyaluronic acid-coated Cu/Mn Prussian blue nanocubes amplify cuproptosis and cGAS-STING signaling for synergistic prostate cancer therapy.
Improved Chemosensitivity in Metastatic Castration-Resistant Prostate Cancer: The Synergistic Effects of S-Adenosylmethionine and Cabazitaxel.
MR-based techniques for imaging prostate cancer metabolism: current status and future perspectives.
Evolving Treatments and Resistance Mechanisms in Prostate Cancer Therapeutics.
Novel therapeutic strategies for metastatic castration‑resistant prostate cancer: Beyond androgen receptor pathway inhibition (Review).
Recent Advances in Understanding the Biology of Castration-Resistant Prostate Cancer.
Casein kinase 1α inhibition reduces prostate cancer cells viability: Role of the autophagy mechanism.
Citrate-functionalised hydroxyapatite mimics the microenvironment of bone metastases and demonstrates the role of citrate in prostate cancer colonization of bone.

Cell Death Differ. 2026 Apr 14.

Role of the cross-regulation between Wnt pathway activation and androgen receptor signaling in prostate cancer treatment resistance.

Nicolas Anselmino, Pablo Sanchis, Juan Bizzotto, Estefania Labanca, Jiabin Dong, Peter D A Shepherd, Jun Yang, Elba S Vazquez, Joaquin Mateo, Geraldine Gueron, Christopher J Logothetis.

Prostate cancer (PCa) is a biologically heterogeneous disease that frequently progresses to castration-resistant prostate cancer (CRPC), a challenging clinical stage. The underlying mechanisms driving CRPC progression and resistance to androgen receptor (AR) signaling inhibition (ARSI) remain incompletely understood. Emerging evidence implicates the canonical Wnt pathway as a key contributor to CRPC progression. This study elucidates the role of Wnt pathway activation in mediating resistance to ARSI and identifies a robust molecular signature for predicting treatment outcomes. By integrating genomic and transcriptomic data from PCa patients, patient-derived xenografts (PDXs), and experimental models harboring or not Wnt-activating mutations, we performed differential expression analysis, unsupervised clustering, survival, and viability analysis to assess Wnt/β-catenin pathway activation and its interaction with AR signaling. A specific Wnt transcriptional signature (AXIN2, RNF43, ZNRF3, NKD1) was found to reliably reflect pathway activation in advanced PCa. AR was found to suppress mutation-driven Wnt signaling, which was upregulated upon AR inhibition, contributing to treatment resistance. Targeting β-catenin interactions with co-activators p300/CBP using selective inhibitors (IQ-1 and ICG-001) effectively mitigated Wnt-driven ARSI resistance, restoring sensitivity to therapy in preclinical models. Thus, canonical Wnt pathway activation emerges as a critical mediator of resistance to ARSI in CRPC. The identified Wnt signature holds potential as a biomarker for predicting and monitoring therapeutic outcomes. Concurrent targeting of AR and Wnt signaling represents a promising strategy to overcome treatment resistance, particularly in patients with Wnt-activating mutations.

DOI: https://doi.org/10.1038/s41418-026-01732-7
Cell Death Dis. 2026 Apr 14.

Aberrant activation of epigenetic BRD9-DGAT1 axis promotes lipid droplets deposition and ferroptosis resistance in YAP-high prostate cancer.

Xuejin Zhu, Zhimei Wen, Jinhai Wu, Sian Chen, Ran Xu, Bin Wang, Yingwen Zhu, Yanfei Chen.

Aberrant interplay between epigenetics and metabolism contributes to prostate cancer (PCa) progression and represents a formidable challenge limiting the efficacy of drugs. Elucidation of the epigenetic underpinnings of prostate cancer (PCa) could provide promising insights into the drivers of therapy resistance. Through an unbiased siRNA screen of mSWI/SNF family members, which play a significant role in tumorigenesis, we identified Bromodomain containing 9 (BRD9) as an essential gene for PCa growth. Targeting BRD9 abolished PCa colony formation and migration in vitro, and inhibited orthotopic tumor growth in vivo. YAP/TEAD4 complex bound to the BRD9 promoter to elevate its levels. Integrated CUT&Tag-seq and RNA-seq analyses revealed DGAT1 as an important BRD9 effector. Mechanistically, BRD9 interacted with SREBP1 to co-occupy the DGAT1 promoter, increasing the H3K4me3 enrichment and chromatin accessibility. Additionally, the YAP-BRD9 axis enhanced the lipid droplets (LDs) formation, ferroptosis resistance, and tumorigenesis via inducing DGAT1. The pharmacological inhibition (or depletion) of BRD9 suppressed LDs formation, restored ferroptosis sensitivity, and PCa malignancy. Overall, the BRD9-SREBP1-DGAT1 axis represents a potential epigenetic therapeutic target for YAP-high PCa.

DOI: https://doi.org/10.1038/s41419-026-08746-6
J Pharmacol Exp Ther. 2026 Mar 23. pii: S0022-3565(26)00519-7. [Epub ahead of print]393(5): 104320

SOX11-mediated CXCL10/CXCR3 activation promotes neuroendocrine prostate cancer.

Hekang Ding, Qingwei Meng, Kun He, Ziqi Chen, Yi Tang, Yige Yang, Xu Wang, Bing Zhao, Lingfan Xu.

  Neuroendocrine prostate cancer is an aggressive, therapy-resistant subtype of prostate cancer with unclear underlying molecular mechanisms and limited effective treatments. Through single-cell transcriptomic analysis, we found that SOX11 is specifically expressed in neuroendocrine cell populations. Further studies confirmed that SOX11 promotes neuroendocrine transdifferentiation in prostate cancer via CXCL10/CXCR3 activation, thereby enhancing the migration and invasion abilities of prostate cancer cells. These results suggest that SOX11 may play a central role in driving neuroendocrine prostate cancer progression, which is expected to serve as a candidate factor for subsequent therapeutic exploration. SIGNIFICANCE STATEMENT: This study reveals the mechanism by which the SOX11/CXCL10/CXCR3 axis promotes neuroendocrine transdifferentiation of prostate cancer, thereby identifying potential targets for the development of targeted therapeutic strategies against neuroendocrine prostate cancer.

Keywords:  CXCL10/CXCR3; Neuroendocrine differentiation; Neuroendocrine prostate cancer; Prostate cancer; SOX11

DOI:  https://doi.org/10.1016/j.jpet.2026.104320
Front Cell Dev Biol. 2026 ;14 1768139

Multi omics network toxicology and in vitro experiments elucidate the role of benzo [a] pyrene in prostate cancer.

Zhenwei Liu, Qingqing Ren, Shanchang Zhou, Guofu Liang.

   Background: In recent years, growing attention has been paid to the role of Benzo [a]pyrene (BaP) in the development and progression of prostate cancer (PCa). However, the specific molecular mechanisms remain unclear. This study aims to explore the potential association between BaP and PCa and to identify key molecular targets that may underlie this relationship, using an integrative bioinformatics approach.
Methods: This study initiated with a computational toxicology assessment of BaP's carcinogenicity and endocrine-disrupting properties using the ProTox 3.0 platform. Subsequently, potential target genes linking BaP to PCa were identified by integrating multiple public databases. The overlapping genes underwent PPI network construction and visualization, followed by GO functional annotation and KEGG pathway enrichment analyses to elucidate the underlying biological mechanisms. Through screening 101 machine learning algorithm combinations, we identified the most relevant key genes associated with PCa progression. Molecular docking technology was then employed to evaluate the binding interactions between BaP/natural active products and these key targets. The CIBERSORT algorithm was utilized to analyze RRM2's regulatory role in the PCa tumor microenvironment, complemented by pan-cancer analysis to investigate RRM2's universal functions across various malignancies. Finally, in vitro cell experiments were conducted for validation.
Results: This study further underscores the carcinogenic properties and endocrine-disrupting effects of BaP. Integration of multi-source databases identified 443 potential BaP-PCa targets. GO and KEGG enrichment analyses revealed that these targets are primarily involved in regulating cell proliferation, inflammatory responses, oxidative stress, and multiple oncogenic signaling pathways. Machine learning algorithm screening showed that the Enet (α = 0.1) model exhibited the best predictive performance and robustness. Through molecular docking, Kaplan-Meier survival analysis, and validation using the Human Protein Atlas (HPA) database, RRM2 was identified as a key regulatory gene and found to play a central role in BaP-mediated immunosuppression processes. Pan-cancer analysis demonstrated that RRM2 has universal functions across various malignancies. Molecular docking results indicated that seven known anti-tumor natural products exhibit significant binding affinity with RRM2. In vitro experiments demonstrated that BaP treatment was associated with increased RRM2 expression in prostate cancer cells, while baicalin treatment reduced this effect, providing preliminary experimental support for the bioinformatic predictions.
Conclusion: This study delineates a potential mechanistic framework by which BaP may be associated with PCa progression through multi-target and multi-pathway mechanisms, highlighting RRM2 as a candidate core mediator. These findings provide a theoretical foundation for future experimental validation and epidemiological studies.

Keywords:  RRM2; benzo[a]pyrene; machine learning framework; network toxicology; prostate cancer

DOI:  https://doi.org/10.3389/fcell.2026.1768139
Front Pharmacol. 2026 ;17 1769906

CRIP1 promotes docetaxel resistance and immune-associated cell death modulation in prostate cancer.

Dehua Zhang, Meiling Han, Ni Yan, Yu Zhang, Chao Wang, Wenzhong Shi, Wenxue Jia, Jun Cao.

   Background: Docetaxel resistance is a major barrier to durable disease control in advanced and castration-resistant prostate cancer. There is a pharmacological need to identify biomarkers that not only stratify resistance risk but also nominate tractable regulators whose perturbation can restore taxane sensitivity and suppress resistant phenotypes.
Methods: We analyzed docetaxel-resistant prostate cancer cell models to derive resistance-associated transcriptional candidates and used computational prioritization to construct a compact, taxane-resistance-anchored gene set. Associations of the gene set and key candidates with disease progression were evaluated in TCGA-PRAD, which predominantly represents treatment-naïve primary tumors and therefore provides progression relevance rather than treatment-specific response validation. Docetaxel-resistant cell lines were established for functional validation, and CRIP1 was stably silenced to assess effects on drug sensitivity, clonogenic growth, migration, apoptosis, and immune-associated cell-death features. In addition, an LNCaP-DTXr xenograft model was used to evaluate the impact of CRIP1 knockdown on docetaxel response in vivo.
Results: A three-gene, taxane-resistance-anchored signature was derived and showed progression-related associations in TCGA-PRAD. Among candidates, cysteine-rich protein 1 (CRIP1) was consistently upregulated in resistant models and emerged as a top resistance-associated factor. Functionally, CRIP1 knockdown restored docetaxel sensitivity, reduced clonogenic survival and migratory capacity, and enhanced docetaxel-induced apoptosis in resistant prostate cancer cells. Consistently, CRIP1 depletion significantly suppressed tumor growth and reduced tumor burden in docetaxel-treated LNCaP-DTXr xenografts, indicating restored chemosensitivity in vivo. In parallel, CRIP1 depletion was accompanied by changes in damage-associated and immune-related cell-death readouts under taxane stress, suggesting a potential role in linking drug tolerance to immune-relevant cell-death programs.
Conclusion: These findings identify CRIP1 as a functionally validated, pharmacologically relevant mediator of docetaxel resistance in prostate cancer. While independent validation in taxane-treated clinical cohorts is warranted, our results support CRIP1 as a candidate therapeutic target and provide a mechanistic framework connecting taxane resistance with immune-associated cell-death modulation.

Keywords:  Crip1; chemotherapy resistance; computational prioritization; docetaxel resistance; drug target; immunogenic cell death; prostate cancer

DOI:  https://doi.org/10.3389/fphar.2026.1769906
Biochem Pharmacol. 2026 Apr 15. pii: S0006-2952(26)00315-1. [Epub ahead of print] 117982

Ailanthone targets the EGR3-SOCS2 regulatory pathway to suppress vasculogenic mimicry in prostate cancer.

Hong Pan, Shuyi Chen, Shanming Ruan, Jiamin Lu, Kai Zhang.

  Prostate cancer (PCa) frequently progresses to castration-resistant stages with poor prognosis, in which vasculogenic mimicry (VM) contributes to tumor aggressiveness and therapeutic resistance. Here, we investigated the antitumor effects of the natural quassinoid Ailanthone (AIL) and its impact on VM in PCa. Our study demonstrates that AIL markedly suppresses PCa cell viability, induces apoptosis and G1/S cell-cycle arrest, and inhibits migration, invasion, stemness, and VM formation. Mechanistically, AIL enhances early growth response protein 3 (EGR3) binding to the promoter of suppressor of cytokine signaling 2 (SOCS2), leading to SOCS2 upregulation and subsequent inhibition of JAK/STAT3 signaling. Functional rescue experiments reveal that SOCS2 or EGR3 silencing partially reverses the inhibitory effects of AIL on malignant phenotypes and VM. In vivo, AIL significantly reduces tumor growth, promotes apoptosis, and attenuates VM formation, effects that are weakened upon SOCS2 knockdown. Collectively, these findings indicate that AIL exerts potent anti-tumor and anti-VM activities in PCa by activating the EGR3-SOCS2 axis and suppressing JAK/STAT3 signaling, highlighting its potential as a promising therapeutic strategy for advanced and treatment-resistant PCa.

Keywords:  Ailanthone; JAK/STAT3 signaling pathway; Prostate cancer; SOCS2; Vasculogenic mimicry

DOI:  https://doi.org/10.1016/j.bcp.2026.117982
Cancer Gene Ther. 2026 Apr 14.

WTAP stabilized by USP7 contributes to enzalutamide resistance in prostate cancer via mediating AKT m6A-modification.

Ruxue Shi, Kai Gu, Haichuan Li, Qingwei Sun, Xinyu Wu, Shuhong Huang, Qingxia Hu.

Castration-resistant prostate cancer (CRPC) is one of the most prevalent cancers in men. The new generation androgen receptor (AR) inhibitor enzalutamide can improve the therapeutic effectiveness of patients with CRPC. However, these patients eventually develop acquired enzalutamide resistance (ENZR), and the mechanisms underlying resistance are not well understood. Wilms' tumor 1-associating protein (WTAP) plays an important role in m6A modification and has been reported as an oncogene in various cancers. Here, we utilized a tissue microarray and collected tissues from prostate cancer (PCa) patients to detect WTAP expression, and found that WTAP is upregulated in PCa. Meanwhile, WTAP overexpression promotes cell proliferation and accelerates tumor growth through colony formation assays and the establishment of a subcutaneous xenograft model in vivo. These findings establish the tumor promoter role of WTAP in prostatic tumorigenesis. Furthermore, we verified that WTAP is a novel responsive gene of AR via promoter activity and chromatin immunoprecipitation (ChIP) assays. Importantly, we uncovered that WTAP is upregulated in ENZR cells, and WTAP knockdown inhibited the proliferation of ENZR cells. Mechanistically, ubiquitin-specific protease (USP7) enhanced the stability of WTAP by the ubiquitin-proteasome pathway in ENZR cells, thereby WTAP increases promote AKT signaling through an m6A-mediated way, and an AKT inhibitor can abolish the pro-resistance phenotype mediated by WTAP. Together, these findings suggest that WTAP plays a key role in ENZR development of PCa cells, and WTAP may be a potential treatment target for ENZR tumors. In this manuscript, we utilized a tissue microarray and collected tissues from prostate cancer (PCa) patients to detect WTAP expression, and found that WTAP is upregulated in PCa. Meanwhile, WTAP overexpression promotes cell proliferation and accelerates tumor growth through colony formation assays and the establishment of a subcutaneous xenograft model in vivo. These findings establish the tumor promoter role of WTAP in prostatic tumorigenesis. Furthermore, we verified that WTAP is a novel responsive gene of AR via promoter activity and chromatin immunoprecipitation (ChIP) assays. Importantly, we uncovered that WTAP is upregulated in ENZR cells, and WTAP knockdown inhibited the proliferation of ENZR cells. Mechanistically, ubiquitin-specific protease (USP7) enhanced the stability of WTAP by the ubiquitin-proteasome pathway in ENZR cells, thereby WTAP increases promote AKT signaling through an m6A-mediated way, and an AKT inhibitor can abolish the pro-resistance phenotype mediated by WTAP. Together, these findings suggest that WTAP plays a key role in ENZR development of PCa cells, and WTAP may be a potential treatment target for ENZR tumors.

DOI: https://doi.org/10.1038/s41417-026-01013-y
Transl Androl Urol. 2026 Mar 15. 15(3): 79

Construction of a survival model for predicting biochemical recurrence of prostate cancer based on propionate metabolism-related genes.

Baosai Lu, Yalin Niu, Xi Liu, Chenming Zhao, Yuewei Yin.

   Background: About 20-40% of prostate cancer (PCa) develop biochemical recurrence (BCR) after surgery, and propionate metabolism may contribute to tumor progression. BCR remains a major clinical challenge in PCa, as current tools based on histopathology and prostate-specific antigen (PSA) fail to capture the molecular heterogeneity driving the disease. While metabolic reprogramming is known to facilitate post-treatment adaptation, the specific role of propionate metabolism in this context remains largely unexplored. Therefore, this study aimed to systematically investigate propionate metabolism-related genes (PMRGs) to develop a novel prognostic model for the improved early prediction of recurrence.
Methods: In this study, The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD), GSE70770 and 412 PMRGs were employed. Differentially expressed genes (DEGs) in PCa and control and DEGs2 in BCR and no BCR samples obtained by differential analysis were intersected with PMRGs to get candidate genes. After Cox and least absolute shrinkage and selection operator (LASSO) regression analyses, biomarkers were identified to construct risk models.
Results: Biomarkers including BMP6, NAT2, PTGS2, LPL were identified to construct risk model after a series of analyses. Meanwhile, the nomogram for risk score can effectively predict BCR-free recurrence in PCa patients. Besides, 16 signaling pathways were significantly associated with riskScore, such as cell cycle and DNA replication. In immune-related analysis, six immune cells were significantly associated with the biomarkers. Furthermore, Wee1 Inhibitor_1046, Paclitaxel_1080, etc. were therapeutic drugs for PCa patients. Finally, the expression trend of four biomarkers was confirmed in clinical samples.
Conclusions: In this study, PMRGs were regarded as biomarkers in PCa for risk model construction, which suggest that propionate metabolism represents a biologically relevant axis in PCa recurrence and may offer a novel framework for biomarker-driven risk assessment.

Keywords:  Prostate cancer (PCa); biochemical recurrence (BCR); nomogram; risk model

DOI:  https://doi.org/10.21037/tau-2025-aw-811
Fitoterapia. 2026 Apr 13. pii: S0367-326X(26)00165-6. [Epub ahead of print] 107246

Mechanistic investigation of Corydalis yanhusuo in prostate cancer: Targeting the miR-192-5p-PI3K/AKT/mTOR and STAT3-HSP90 pathways.

M Maharub Hossain Fahim, Changhyun Kim, Hyo Jeong Kim, Nahida Aktary, Jinwon Choi, Min Choi, Trina E Tallei, Oussama Bekkouch, Moon Nyeo Park, Bonglee Kim.

  Prostate cancer remains a major cause of cancer-related mortality, with therapeutic resistance frequently driven by aberrant oncogenic signaling and epithelial-mesenchymal transition (EMT). MicroRNAs (miRNAs), such as miR-192-5p, have emerged as important regulators of tumor progression and drug resistance. Corydalis yanhusuo (CDY), a traditional medicinal herb widely used in East Asia, exhibits a range of pharmacological properties, but its molecular mechanisms of action in prostate cancer are not yet fully defined. In this study, we integrated phytochemical profiling, high-performance liquid chromatography / Liquid chromatography-mass spectrometry (HPLC/LC-MS), in silico molecular docking, network pharmacology, and in vitro and semi-in vivo functional assays to investigate the anti-cancer effects of CDY. Major bioactive compounds, including quercetin, corydaline, and dehydrocorydaline were identified, showing high binding affinity to key oncogenic proteins such as Epidermal growth factor receptor (EGFR), Protein Kinase B (AKT), Phosphoinositide 3-kinase (PI3K), Signal transducer and activator of transcription 3 (STAT3), and Heat shock protein 90 (HSP90). CDY significantly suppressed colony formation and cell migration in DU145 and PC-3 prostate cancer cells, reversed EMT phenotypes by reducing lamellipodia formation and restoring epithelial morphology, and regulated EMT-associated markers. Western blot analysis demonstrated inhibition of EGFR/PI3K/AKT/mTOR (mechanistic Target of Rapamycin) and STAT3/HSP90 signaling, along with marked downregulation of PI3K and phosphorylation levels of EGFR, AKT, and STAT3. CDY also upregulated miR-192-5p expression, which correlated with suppression of EMT-related transcription factors. In the chick chorioallantoic membrane (CAM) assay, CDY inhibited tumor growth and angiogenesis, with enhanced effects in PC-3 cells. These findings suggest that CDY exerts multi-targeted anti-cancer effects by modulating oncogenic signaling pathways and epigenetic regulators, supporting its potential as a promising bioactive lead for prostate cancer. Collectively, these findings demonstrate that CDY exerts mechanistically coordinated anticancer effects in vitro and in chorioallantoic membrane (CAM) models, warranting further validation in mammalian in vivo systems to assess translational relevance.

Keywords:  Corydalis yanhusuo; EGFR/PI3K/AKT/mTOR signaling; Epithelial–mesenchymal transition; Prostate cancer; STAT3/HSP90 axis; miR-192-5p

DOI:  https://doi.org/10.1016/j.fitote.2026.107246
Cancers (Basel). 2026 Apr 01. pii: 1137. [Epub ahead of print]18(7):

G Protein-Coupled Oestrogen Receptor Actions Targeting the Hallmarks of Cancer in Human Prostate Cells: From Cell Fate to Metabolic Reprogramming.

Marília I Figueira, Henrique J Cardoso, Lara R S Fonseca, Tiago M A Carvalho, Sara Correia, Patrícia Arinto, Rui Henrique, Adriana O Santos, Cláudio J Maia, Sílvia Socorro.

  Background/Objectives: The G protein-coupled oestrogen receptor (GPER) has anti-tumorigenic effects in several human cancers. However, its role in prostate cancer (PCa) remains incompletely defined. The present study investigated GPER's role in targeting the hallmarks of PCa. Methods: Tissue microarrays were used to analyse GPER immunoexpression in PCa samples. Non-neoplastic (PNT1A) and neoplastic (LNCaP, DU145 and PC3) prostate cells were treated with the GPER-specific agonist, G1. Cell viability, proliferation, cell cycle, apoptosis, migration and invasion were evaluated. Glucose consumption, lactate production, lactate dehydrogenase activity and oxidative status were determined spectrophotometrically. Results: GPER immunoreactivity was higher in PCa than in benign prostatic hyperplasia and inversely correlated with PSA serum levels. G1 modulated GPER subcellular location in prostate cells, being detected at the cell membrane, endoplasmic reticulum, and residually in the nucleus. GPER activation decreased cell viability and proliferation, induced cell cycle arrest at G2/M phase, and increased PCa cells apoptosis. Additionally, GPER activation inhibited the migration and invasion of DU145 cells, and long-term exposure to G1 reduced epithelial-mesenchymal transition, an effect not observed in PC3 cells, indicating the importance of cell-specific contexts. Our results also showed that G1 treatment modulated the metabolic profile of PCa cells, changing glucose, amino acids and lipid metabolism. Finally, G1 increased oxidative stress in PCa cells. Conclusions: Overall, this study demonstrated that GPER activation affects a broad range of PCa hallmarks. These findings support an anti-cancer role for GPER in PCa and encourage further exploration of its action in regulating metabolism and as a therapeutic target.

Keywords:  G protein-coupled oestrogen receptor (GPER); apoptosis; metabolism; migration and invasion; oxidative stress; proliferation; prostate cancer (PCa)

DOI:  https://doi.org/10.3390/cancers18071137
World J Urol. 2026 Apr 13. pii: 303. [Epub ahead of print]44(1):

Comparison of prostate cancer diagnostic models based on PCA3 and TMPRSS2:ERG RNA biomarkers from post-DRE and non-DRE urine specimens.

Mantvydas Lopeta, Sigitas Paliksa, Jonas Belevicius, Mindaugas Ukanis, Laura Kasiliauskiene, Laura Dziuge, Ingrida Zutautaite-Varela, Marija Barisiene, Arnas Bakavicius, Ramunas Mickevicius, Arvydas Zykus, Albertas Ulys, Linas Juodele, Feliksas Jankevicius, Mindaugas Jievaltas, Julius Gagilas.



Keywords:  Biomarkers; Prostate; Prostate cancer; Prostate massage; Tumour Biomarkers; Urinalysis

DOI:  https://doi.org/10.1007/s00345-026-06396-z
Nat Prod Res. 2026 Apr 11. 1-7

α-mangostin, a xanthone from garcinia mangostana fruit inhibits MEK1 kinase in prostate cancer.

Pariksha Thapa, Kanchan Yadav, Pradeep Subedi, Jeremy J Johnson.

  Prostate cancer is the second most common malignancy in men in the United States. Although second-generation anti-androgens are initially effective, eventually drug resistance develops. Hyperactivation of MEK1, a central gatekeeper protein in MAPK pathway, is observed in prostate cancer. Recently, targeting MEK1 has been a fascinating area of research. Here, our data reports that mangosteen xanthones can inhibit MEK1 kinase using a cell-free biochemical assay. Among nine xanthones, γ-mangostin and α-mangostin were most potent, and the presence of an isoprenyl group at position 8 was the key structural difference that can contribute to MEK1 inhibition. Furthermore, α-mangostin dose-dependently inhibited the p-MEK1/2(Ser217/221) and downstream target p-MSK1(Thr581) in both 22Rv1 and PC3 prostate cancer cells. The molecular docking result aligned with our findings of the inhibition assay showing a strong correlation. Taken together, the results suggest that xanthones can directly target MEK1, providing a possible opportunity for their therapeutic potential in prostate cancer.

Keywords:  MAPK pathway; MEK1; Prostate cancer; alpha-mangostin; mangosteen

DOI:  https://doi.org/10.1080/14786419.2026.2648811
Br J Cancer. 2026 Apr 15.

SUMOylation of EphB4 enhances its stability in prostate cancer.

Mohanan Sada Nand Maharaj, Inga Mertens-Walker, Jessica E Lisle, Adrian Herington, Carson Stephens, Melissa Chai, Wim Meutermans, Sally-Anne Stephenson.

BACKGROUND: The receptor tyrosine kinase EphB4 is frequently overexpressed in epithelial cancers, including prostate cancer (PCa). SUMOylation is a post-translational modification that influences protein interactions, localisation and stability. This study investigated how SUMOylation regulates EphB4 localisation, stability and function in PCa.
METHODS: EphB4 SUMOylation was analysed in PCa cell lines and its contribution to stability assessed using siRNA or chemical inhibition of SUMOylation. An EphB4 mutant protein (K616R) was expressed in PCa cells and proteasomal inhibition was used to assess its stability. Cell migration was measured using a scratch wound assay. Immunoprecipitation was used to determine if mutant EphB4 could be SUMOylated on other residues.
RESULTS: EphB4 in PCa cells is constitutively modified by SUMO2/3 and acquires SUMO1 modification when stimulated with ephrin-B2 ligand. SUMOylation of K616 is critical for EphB4 stability. K616R EphB4 protein is degraded by the proteasome, and this is associated with reduced MYC protein and slower migration. Immunoprecipitation revealed that additional SUMOylated lysines may also contribute to EphB4 function.
CONCLUSIONS: SUMOylation at K616 stabilises EphB4, promotes MYC signalling and PCa cell migration. These findings identify a novel mechanism regulating EphB4 and highlight SUMOylation as a potential target in EphB4-driven cancers.

DOI: https://doi.org/10.1038/s41416-026-03442-w
Endocrinology. 2026 Apr 17. pii: bqag046. [Epub ahead of print]

Intersection of Phenotypic Plasticity and Anoikis Enhances Therapeutic Vulnerability in Prostate Cancer.

Maria Kouspou, Alec Zhu, Lauren Martires, Ashutosh K Tewari, Reza Mehrazin, Natasha Kyprianou.

  During cancer metastasis, tumor cells survive in circulation by acquiring resistance to anoikis. Restoring vulnerability of cancer cells to anoikis can impair metastatic colonization, minimize treatment resistance and tumor recurrence in patients. A compelling body of evidence has identified strategies for the development of effective inhibitors that can block survival pathways such as FAK, PI3 K/AKT, MAPK and integrin signaling to prevent prostate cancer cells from leaving the primary tumor/site and/or to impair their colonization at secondary sites. Transcriptomic profiling recently identified anoikis-centered genes, including CDKN1A, NEDD9, CFL1, and JAM2, that may have potential prognostic value in prostate cancer progression and may also contribute to the emergence of therapeutic resistance to antiandrogens and taxane chemotherapy. Direct cytoskeletal remodeling by cofilin, a transforming growth factor-β (TGF-β) effector is linked to phenotypic plasticity changes. NEDD9 causes cytoskeletal dynamics through signaling pathways and it is correlated with tumor aggressiveness. CDKN1A affects cell cycle regulation, and JAM2 influences cell adhesion. This review interrogates the current evidence in the literature on the cellular drivers of anoikis resistance, intersecting with phenotypic plasticity in the prostate tumor microenvironment (TME), towards determination of the underlying molecular mechanisms that can be exploited at the translational level for therapeutic applications. The identification and subsequent validation of novel anoikis-resistance based signatures can be of potential value as predictive markers of therapy resistance and tumor recurrence in patients with advanced prostate cancer.

Keywords:  molecular signatures; therapeutic vulnerability; tumor progression

DOI:  https://doi.org/10.1210/endocr/bqag046
Urology. 2026 Apr 14. pii: S0090-4295(26)00243-8. [Epub ahead of print]

Varicocele and Untreated Hypogonadism Synergistically Increase Prostate Cancer Risk via Testosterone Shunt Physiology and can be Ameliorated with Testosterone Therapy.

Bryan D Naelitz, Jayant Siva, Sanjay Vallabhaneni, Leila Momtazi-Mar, James M Hotaling, Scott D Lundy, Joshua J Horns.

OBJECTIVES: To evaluate whether varicocele modifies the relationship between hypogonadism and incident prostate cancer. Venous shunting of testosterone-enriched blood from the testicle to the dorsal venous complex occurs in ~20% of men and has been linked to prostate cancer progression. Although hypogonadism has been inconsistently linked to prostate cancer risk, the influence of varicocele remains unexplored.
MATERIALS AND METHODS: Using the Merative MarketScan database, we identified men >40 years with varicocele and matched them by age and follow-up interval to two cohorts: (1) a general population cohort and (2) men with benign scrotal pathology associated with urological assessment. Time to prostate cancer was assessed using Cox proportional hazards models adjusted for age, obesity, rurality, family history, hypogonadism status, testosterone therapy, and varicocele status. An interaction term between varicocele and hypogonadism was included.
RESULTS: Among 149,848 men (75,673 varicocele and 74,175 scrotal pathology controls), varicocele was associated with a higher incidence of prostate cancer (4.4 vs 3.8%, p<0.01) and hypogonadism (13.3 vs 11.2%, p<0.01). In adjusted models, varicocele alone was not associated with prostate cancer risk (HR: 1.04, p=0.18). Untreated hypogonadism was associated with a modestly increased risk of incident prostate cancer (HR: 1.27, p<0.01). Men with both varicocele and untreated hypogonadism experienced the highest hazard of incident prostate cancer (HR: 1.31, p<0.001).
CONCLUSION: Varicocele amplifies the risk of prostate cancer associated with untreated hypogonadism. Testosterone therapy and possibly varicocelectomy mitigate this effect, supporting the notion that venous testosterone shunting to the prostate occurs in a subset of men.

DOI: https://doi.org/10.1016/j.urology.2026.04.016
Cells. 2026 Apr 02. pii: 647. [Epub ahead of print]15(7):

Single-Cell and Spatial Transcriptomics Reveal That TXNIP and BIRC3 Contribute to Human Prostate Tumor Progression.

Seyed Taleb Hosseini, Hossein Azizi, Thomas Skutella.

  Prostate cancer is one of the most prevalent malignancies among men and remains a major clinical challenge due to the complex tumor microenvironment. Understanding gene expression dynamics at both cellular and spatial levels is essential for improving therapeutic strategies. In this study, we performed an integrated multi-omics analysis using single-cell RNA sequencing and spatial transcriptomics. scRNA-seq data from 15 prostate samples, including 8 normal and 7 tumor tissues, were analyzed to characterize distinct cellular populations. Spatial transcriptomic profiling was conducted on three FFPE prostate tissue sections, including adjacent normal tissue, acinar cell carcinoma, and invasive adenocarcinoma, using the standard 10x Genomics Visium FFPE platform (55 µm capture spots). Single-cell analysis revealed heterogeneity among epithelial, stromal, and immune cell populations, highlighting complex signaling networks in which myeloid cells may contribute to tumor progression through immune suppression and epithelial adaptability. Spatial transcriptomic analysis further identified region-specific expression patterns and spatially restricted tumor niches, including the regional establishment of TXNIP and BIRC3 as genes associated with metabolic stress and inflammatory survival pathways. The spatial colocalization of BIRC3 with tumor vasculature in invasive carcinoma tissue suggests a novel interaction. Our discoveries using an integrated single-cell and spatial transcriptomic approach reveal a high-resolution molecular map of prostate cancer with spatial features that may provide further therapeutic investigation.

Keywords:  biomarker discovery; precision oncology; prostate cancer; single-cell RNA seq; spatial transcriptomics; tumor heterogeneity

DOI:  https://doi.org/10.3390/cells15070647
Prostate. 2026 Apr 17.

Protein Kinase D1 Translocates PARP1 to the Membrane and Is Associated With Increased Sensitivity to Cell Viability Inhibition by PARP1 Inhibitor Olaparib.

Sanjeev Shukla, Joseph McGrath, Robert Willis, Arjun Venkatesh, Reynier D Rodriguez Rosales, Jean-Pierre Kanumuambidi, Mario Mietzsch, Robert McKenna, Jonathan Chardon-Robles, K C Balaji.

   BACKGROUND: There are four FDA-approved poly (ADP-ribose) polymerase inhibitors (PARPi) for treating metastatic castration-resistant prostate cancer. However, dose-limiting toxicities may reduce efficacy when treatment is de-escalated. Identifying modulators of PARPi sensitivity could enable combination strategies that enhance efficacy while minimizing toxicity. This study investigates whether Protein kinase D1 (PrKD1), recently discovered to modulate DNA repair, influences sensitivity to PARP inhibition.
METHODS: We used prostate cancer cell lines with altered PrKD1 expression to assess viability following olaparib and/or Compound-10, a selective PrKD1 inhibitor, treatment. Subcellular fractionation, immunoprecipitation, in silico modeling and Western blotting of lysates of cells and tumor samples harvested from patient-derived xenograft tumor engrafted mice treated with Compound-10 were used to evaluate protein expression, interaction, and localization.
RESULTS: PrKD1-overexpressing C4-2 cells exhibited significantly increased sensitivity to growth inhibition by olaparib. Downregulation of PrKD1 in LNCaP cells conferred resistance. Biochemical inhibition of PrKD1 by Compound-10 also enhanced sensitivity. Co-immunoprecipitation experiments demonstrated that PrKD1 and PARP1 are present in the same immunocomplex, and PrKD1 transfection in C4-2 cells increased PARP1 membrane localization. Treatment of prostate cancer PDX models with Compound-10 increased PARP1 expression. In silico molecular modeling identified a site adjacent to the PARP1 WGR domain potentially binding to multiple PrKD1 domains.
CONCLUSION: Our study identifies PrKD1 as a novel modulator of sensitivity to olaparib. Co-targeting PrKD1 using small molecular inhibitors may enhance olaparib efficacy at lower doses and improve PARPi tolerability and therapeutic index. The demonstration of PARP1 at the membrane is novel, introducing the possibility of targeting membranous PARP1 for theranostic applications.

Keywords:  DNA damage response; PARP inhibitors; drug discovery; prostatic neoplasms

DOI:  https://doi.org/10.1002/pros.70182
Comput Struct Biotechnol J. 2026 ;35(1): 0038

Identification of a Novel Trifluoromethyl-Bearing Flavonoid as a Promising Androgen Receptor Antagonist: Structure-Based Virtual Screening and In Vitro Study.

Phakkhathorn Tadasee, Tanatorn Khotavivattana, Kulathida Chaithirayanon, Suvichada Assawakosri, Bodee Nutho.

Aberrant androgen receptor (AR) expression is the primary driver of prostate cancer progression. While androgen deprivation therapy and AR antagonists are the cornerstones of AR-signaling suppression, their long-term efficacy is frequently compromised by adverse effects and the emergence of drug resistance. Consequently, there is an urgent need to identify novel therapeutic agents. In this study, we screened a library of 112 nonsteroidal compounds (flavonoids and chalcones derivatives) using an integrative in silico and in vitro approach. Initial molecular docking revealed that compounds 18ad, 18ai, and 18aj possessed markedly favorable docking scores than the clinical reference, enzalutamide. Subsequent 300-ns molecular dynamics simulations supported the structural stability of these complexes and identified critical interacting residues, including L704, G708, M742, M745, V746, M749, F764, L873, and T877. Notably, in vitro assays demonstrated that compound 18ad, a flavone derivative bearing a trifluoromethyl group, substantially suppressed the proliferation of androgen-dependent (LNCaP) cells. Furthermore, 18ad treatment effectively down-regulated the expression of both the AR and its primary downstream transcriptional target, prostate-specific antigen. Collectively, these findings highlight compound 18ad as a promising lead scaffold for the development of targeted AR therapies for prostate cancer management.

DOI: https://doi.org/10.34133/csbj.0038
Phytomedicine. 2026 Apr 01. pii: S0944-7113(26)00377-6. [Epub ahead of print]155 158143

Betulinic acid induces lysosome-dependent death in prostate cancer by targeting DDX5.

Shoushi Liu, Xiaolan Li, Zhiping Cheng, Kaili Zhao, Yanting Wang, Yuhe Wei, Yuanshuo Wang, Jinjian Lu, Xin Yang, Yang Mooi Lim, Qinpei Lu, Qiuju Huang, Hongwei Guo.

   BACKGROUND: Prostate cancer (PCa) represents a leading cause of cancer-related mortality in men. Betulinic acid (BA) exhibits antitumor properties. However, its direct molecular target and mechanism in PCa remain unclear.
PURPOSE: To identify BA's molecular target and elucidate its mechanism in inhibiting PCa progression.
STUDY DESIGN: In vitro and in vivo models were employed to evaluate BA's antitumor effects and underlying mechanisms.
METHODS: BA's antitumor activity was assessed in PCa cell lines and xenograft models. Apoptosis was examined via Hoechst staining, flow cytometry, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Lysosomal membrane permeabilization (LMP) was examined via LysoTracker Red and acridine orange (AO) staining, validated by CA074-Me. Target identification utilized pull-down assays, drug affinity responsive target stability (DARTS), molecular docking, and microscale thermophoresis (MST). Clinical data analysis and siRNA knockdown confirmed DDX5's role.
RESULTS: BA significantly suppressed PCa growth in vitro and in vivo without toxicity. BA directly bound DDX5, inhibiting transcription factor EB (TFEB)-mediated lysosomal biogenesis and downregulating V-ATPase subunit H (ATP6V1H), essential for lysosomal acidification. This disruption induced LMP and lysosome-dependent cell death (LDCD) via apoptosis, confirmed by CA074-Me. DDX5 expression was decreased in PCa tissues. DDX5 knockdown abolished BA-induced LDCD and lysosomal dysfunction.
CONCLUSION: BA directly targets DDX5, inducing LDCD through the novel BA-DDX5-TFEB-ATP6V1H axis, exploiting lysosomal vulnerability in PCa. These findings underscore BA's therapeutic potential and propose lysosomal membrane destabilization as a precision treatment strategy for PCa.

Keywords:  Betulinic acid; DEAD-box helicase 5 (DDX5); Lysosomal membrane permeabilization (LMP); Lysosome-dependent cell death (LDCD); Prostate cancer (PCa)

DOI:  https://doi.org/10.1016/j.phymed.2026.158143
Eur J Med Chem. 2026 Apr 02. pii: S0223-5234(26)00269-2. [Epub ahead of print]311 118824

Dual BRD4/AKT inhibition overcomes c-MYC-driven resistance in metastatic castration-resistant prostate cancer.

Fuao Zhang, Dezhong Guan, Wenjing Zhang, Yashi Zhou, Jinpei Zhou, Huibin Zhang, Hongbo Wang, Jingwei Tian, Yifei Yang.

Metastatic castration-resistant prostate cancer (mCRPC) represents the terminal and most challenging stage of prostate cancer progression, characterized by limited therapeutic options and poor prognosis. Although AKT inhibitors have been explored as a potential treatment strategy for mCRPC, their efficacy as monotherapy is often constrained by the rapid development of resistance. Emerging evidence indicates that this acquired resistance is frequently associated with the elevated expression of the c-MYC oncogene. Bromodomain and extraterminal (BET) inhibitors, such as those targeting BRD4, can disrupt the interaction between BRD4 and chromatin, thereby attenuating c-Myc-driven oncogenic signaling. To address this dual-pathway challenge, we designed and synthesized a novel series of dual BRD4/AKT inhibitors. Through structure-activity relationship analyses, compound 21d was identified as a potent dual inhibitor, exhibiting activity against both BRD4 and AKT1 with IC50 values of 66.12 ± 7.69 nM and 143.81 ± 12.21 nM, respectively. In vitro, 21d effectively modulated key downstream effectors of both AKT1 and BRD4, leading to significant suppression of mCRPC cell proliferation, migration, and colony formation. Mechanistically, 21d induced G0/G1 phase cell-cycle arrest by downregulating phosphorylated RB (p-RB), cyclin E1, and CDK2. Concurrently, 21d elevated the protein levels of the autophagy marker LC3B, promoting apoptosis in 22Rv1 cells. In vivo, 21d demonstrated a favorable pharmacokinetic profile and markedly inhibited tumor growth in an mCRPC xenograft mouse model, achieving a tumor growth inhibition (TGI) rate of 62.0%. Collectively, our findings establish 21d as the first-in-class dual BRD4/AKT inhibitor, offering a promising therapeutic strategy to overcome c-Myc-associated resistance in mCRPC.

DOI: https://doi.org/10.1016/j.ejmech.2026.118824
Int J Biol Macromol. 2026 Apr 14. pii: S0141-8130(26)01962-8. [Epub ahead of print] 152036

Hyaluronic acid-coated Cu/Mn Prussian blue nanocubes amplify cuproptosis and cGAS-STING signaling for synergistic prostate cancer therapy.

Xiaobing Yao, Yuan Ruan, Ting Rao, Fangyou Lin, Wenbin Zhang.

  Prostate cancer is a prevalent immune-cold malignancy in which hypoxia and glutathione (GSH) enrichment hinder redox-dependent therapies and cuproptosis. A hyaluronic-acid-coated copper-manganese Prussian blue nanomedicine (Cu/Mn-PB@HA) was developed to remodel the tumor microenvironment (TME) and enhance mitochondria-associated cuproptosis. The multivalent Cu/Mn centers enable catalase-like O2 generation, GSH-oxidase-like depletion of GSH, and Fenton-like ·OH production, which together enhance chemodynamic therapy (CDT) and create a favorable window for cuproptosis. In acidic and GSH-rich conditions, copper valence cycling initiates cuproptosis, whereas released Mn2+ enhances CDT and activates the cGAS-STING pathway, thereby promoting dendritic-cell maturation and cytotoxic T-cell responses. The HA shell enables CD44-mediated enrichment, improving tumor accumulation without compromising biosafety. In vitro, the platform elevates ROS, induces mitochondrial depolarization, downregulates HIF-1α, and modulates cuproptosis-related proteins. Concurrently, immunogenic cell-death markers are elevated together with cGAS-STING signaling. In vivo, preferential tumor accumulation and significant tumor inhibition are achieved with favorable serum biochemistry and hepatic/renal histology. By integrating "oxygenation-desensitization-ROS" chemistry with Mn2+- enhanced immune activation, Cu/Mn-PB@HA provides a comprehensive strategy for treating immune-cold solid tumors and serves as a versatile platform for theranostic development.

Keywords:  Cuproptosis; Prostate cancer; cGAS-STING signaling

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152036
Cancer Med. 2026 Apr;15(4): e71784

Improved Chemosensitivity in Metastatic Castration-Resistant Prostate Cancer: The Synergistic Effects of S-Adenosylmethionine and Cabazitaxel.

Roberta Arpino, Francesca Cadoni, Cristina Pagano, Laura Coppola, Vitale Del Vecchio, Aditya Nigam, Laura Mosca, Marina Porcelli.

  Metastatic castration-resistant prostate cancer (mCRPC) is the most aggressive kind of prostate cancer (PCa). Because the traditional taxane-based therapy is ineffective, cabazitaxel (CBZ), a second-generation, semisynthetic taxane, has been developed. Despite it demonstrating efficacy in patients resistant to docetaxel and paclitaxel, two commonly used taxanes, and representing one of the second-line therapeutic options for patients with mCRPC, CBZ has limitations, including considerable side issues and reduced drug susceptibility that gradually emerge and constitute the primary cause of therapeutic failure. For the purposes of this study, the application of nature-derived adjuvants in chemotherapy is emerging as a promising area of research. S-Adenosyl-L-methionine (AdoMet) is a naturally occurring sulfur-containing nucleoside that serves as the major methyl donor for numerous methyltransferases, which is a key metabolite in the cell, participating in a broad range of essential biochemical processes. In the current research, we bring attention to the effectiveness of the combination of AdoMet and CBZ during treatment of mCRPC cells. Using mCRPC cell lines DU 145 and PC-3, we found that the combination of CBZ and AdoMet worked better than either agent alone in suppressing cancer cell growth. This synergistic effect may be mediated by increased production of reactive oxygen species (ROS) and a weakening of the cancer cells' antioxidant defenses, including reductions in glutathione, GPX4, and catalase. The resulting oxidative stress caused DNA damage and interference with mitotic spindle assembly, which induces cell cycle arrest and programmed cell death. These data indicate that AdoMet is capable of intensifying CBZ responsiveness in mCRPC cells, making the treatment more effective.

Keywords:  S‐adenosyl‐L‐methionine; adjuvant chemoterapy; apoptosis; cabazitaxel; metastatic castration‐resistant prostate cancer; oxidative stress

DOI:  https://doi.org/10.1002/cam4.71784
Abdom Radiol (NY). 2026 Apr 12.

MR-based techniques for imaging prostate cancer metabolism: current status and future perspectives.

Xueqing Cheng, Jinshun Xu, Jin Yao, Bin Song.

  Prostate cancer (PCa) is a heterogeneous disease ranging from indolent to highly aggressive forms (e.g., castration-resistant PCa). Although multiparametric MRI plays an important role in the routine diagnosis and management of PCa, emerging challenges underscore a critical unmet need in the era of precision and personalized medicine. Given that metabolic reprogramming is a hallmark of PCa, metabolic imaging techniques that focus on and target changes in metabolic pathways, such as PET and hyperpolarized (HP) 13C MRI, represent critical tools for facilitating early diagnosis, risk stratification, and monitoring of PCa treatment. This review discusses the metabolic characteristics of PCa, the current landscape of MR-based metabolic imaging techniques, and their applications to PCa, with a particular emphasis on recent advances in proton magnetic resonance spectroscopy imaging (1H-MRSI), HP 13C MRI, and other emerging advanced MRI techniques, including chemical exchange saturation transfer (CEST) MRI, sodium (23Na) MRI, and deuterium metabolic imaging (DMI). Additionally, we discuss the challenges and future perspectives for their further clinical translation.

Keywords:  Hyperpolarized 13C MRI; Magnetic resonance spectroscopy; Metabolic imaging; Metabolic reprogramming; Prostate cancer

DOI:  https://doi.org/10.1007/s00261-025-05373-1
ACS Pharmacol Transl Sci. 2026 Apr 10. 9(4): 815-838

Evolving Treatments and Resistance Mechanisms in Prostate Cancer Therapeutics.

Gali Sri Venkata Sai Rishma Reddy, Anuj Kumar, Neeraj Kumar Sharma, Krishna Samanta, Debabrata Pramanik, Naga Bhushana Rao Karampudi, Pulak Kar.

  Prostate cancer remains a leading cause of cancer-related morbidity and mortality among men, fundamentally driven by gain-of-function alterations in the androgen receptor (AR) signaling axis. Although major therapeutic advances from androgen deprivation therapy to next-generation antiandrogens have significantly improved clinical outcomes, disease progression and the emergence of therapeutic resistance continue to pose substantial clinical challenges. This review provides a comprehensive overview of historical and contemporary treatment strategies in prostate cancer with particular emphasis on the molecular mechanisms underlying therapeutic resistance and disease evolution. To support the narrative presented in this review, we incorporate selected in silico analyses, such as molecular docking studies of antiandrogen AR interactions, which are intended to complement published structural and functional studies and provide a mechanistic context to the reviewed literature. In addition, we highlight emerging and evolving therapeutic modalities, including adoptive cell therapy, nanomedicine-based drug delivery, poly-(ADP ribose) polymerase (PARP) inhibition, proteolysis-targeting chimera (PROTAC) technologies, and RNA-based approaches, with emphasis on their translational potential and current limitations. By integrating the existing literature with targeted in silico insights, this perspective presents a forward-looking perspective on overcoming resistance and advancing precision therapeutics in prostate cancer.

Keywords:  androgen deprivation therapy; androgen receptor; antiandrogen resistance; molecular docking; prostate cancer; therapeutics

DOI:  https://doi.org/10.1021/acsptsci.5c00757
Int J Oncol. 2026 Jun;pii: 69. [Epub ahead of print]68(6):

Novel therapeutic strategies for metastatic castration‑resistant prostate cancer: Beyond androgen receptor pathway inhibition (Review).

Yaqin Wang, Yongqiang Xie, Qiang Zhao.

  Metastatic castration‑resistant prostate cancer (mCRPC) remains a lethal disease due to universal resistance to androgen‑receptor pathway inhibitors (ARPI). Tumor progression is orchestrated by a spectrum of androgen‑receptor‑independent drivers, including genomic alterations in DNA damage repair pathways, epigenetic shifts promoting lineage plasticity, metabolic adaptations and an immunosuppressive tumor microenvironment. This evolving understanding has catalyzed the development of novel therapeutic strategies. These include PARP inhibitors for tumors with homologous recombination repair deficiencies, protein kinase B inhibitors for the phosphatase and tensin homolog‑loss subset, prostate‑specific membrane antigen (PSMA)‑targeted radioligand therapy, bispecific T‑cell engagers, antibody‑drug conjugates and immune checkpoint inhibitors. Furthermore, liquid biopsy profiling, PSMA‑positron emission tomography‑based radiomics and artificial intelligence platforms are enhancing real‑time patient selection and response assessment. The present review synthesized these recent preclinical and clinical advances to delineate biomarker‑driven, mechanism‑based therapeutic sequencing and combination strategies for mCRPC in the post‑ARPI era.19.

Keywords:  CDK12 loss; antibody‑drug conjugates; bispecific antibodies; metastatic castration‑resistant prostate cancer; poly (ADP‑ribose) polymerase inhibitors; prostate‑specific membrane antigen theranostics; protein kinase B blockade

DOI:  https://doi.org/10.3892/ijo.2026.5882
Urol Clin North Am. 2026 May;pii: S0094-0143(26)00012-1. [Epub ahead of print]53(2): 303-315

Recent Advances in Understanding the Biology of Castration-Resistant Prostate Cancer.

David Lluís, Wanli Cheng, Josep Maria Piulats, Lucía Heras, Álvaro Aytes, Marianna Kruithof de Julio.

  Prostate cancer progression is largely driven by androgen receptor signaling. While androgen deprivation therapy remains a cornerstone of treatment, it imposes a selective pressure that ultimately leads to the emergence of a castration-resistant phenotype, driven by a range of adaptive molecular mechanisms. In recent years, significant advances have been made in understanding its complex biology, making it a critical focus of ongoing research. The application of multi-omics approaches has played a pivotal role in uncovering the molecular underpinnings of this disease, offering deeper insights into its heterogeneity and resistance mechanisms.

Keywords:  Androgen receptor; Castration-resistant mechanisms; Prostate cancer; Review

DOI:  https://doi.org/10.1016/j.ucl.2026.02.012
Urol Oncol. 2026 Apr 14. pii: S1078-1439(26)00063-3. [Epub ahead of print] 111052

Casein kinase 1α inhibition reduces prostate cancer cells viability: Role of the autophagy mechanism.

Hamid Behrouj, Shahrbanoo Zabihi, Mehrsa Alsadat Taghavi Asl, Negar Noorbakhsh, Ahmad Movahedpour, Ali Veisi, Vahid Zarezade, Mohamad Sabaghan, Omid Azadbakht.

   PURPOSE: Modulation of autophagy in cancer treatment has attracted considerable interest, as it can contribute to cell death. Several studies have shown that inhibition of casein kinase 1α (CK1α) induces autophagy-mediated cell death in various cancer cell lines. As the role of CK1α in autophagy regulation and cell death in prostate cancer (CaP) cell lines remains unclear, this study aimed to investigate it.
MATERIALS AND METHODS: Three human CaP cell lines, LNCaP, PC3, and DU145, were used in this study. Real-time PCR was conducted to determine the basal mRNA expression of CK1α and autophagy markers, including ULK1, WIPI1, LC3B, and p62, in the CaP cell lines. The MTT assay was used to measure the cytotoxic effect of the CK1 inhibitor D4476 (0-500 µM) in LNCaP and PC3 cell lines, both alone and after pretreatment with the autophagy inhibitor wortmannin (1 µM), for 48 hours. To investigate the effect of CK1α inhibition on the expression of autophagy-related genes, D4476 at doses of 62.5 and 31.25 µM for the LNCaP cell line and at doses of 31.25 and 15.62 µM for the PC3 cell line was added to the culture medium, both alone and after pretreatment with wortmannin (1 µM), for 48 hours. The mRNA levels of autophagy markers were then quantified by real-time PCR.
RESULTS: Our results showed that, at the basal level compared to the LNCaP cell line, the PC3 and DU145 cell lines upregulated CK1α mRNA expression while downregulating mRNA levels of autophagy markers. We also found that CK1α inhibition reduced the viability of LNCaP and PC3 cell lines in a dose-dependent manner, accompanied by increased expression of autophagy-related genes in the LNCaP cell line and their downregulation in the PC3 cell line. Furthermore, our data showed that pretreatment with wortmannin differentially modulated the effects of D4476, potentiating them in PC3 cells while having no effect in LNCaP cells.
CONCLUSIONS: Our findings demonstrate that CK1α differentially regulates autophagy in CaP cell lines in a cell type-dependent manner. These results suggest that CK1α inhibition promotes pro-death autophagy in LNCaP cells while suppressing pro-survival autophagy in PC3 cells, highlighting CK1α as a potential therapeutic target in CaP management.

Keywords:  Autophagy; CK1α; Cell death; Prostate cancer

DOI:  https://doi.org/10.1016/j.urolonc.2026.111052
Acta Biomater. 2026 Apr 15. pii: S1742-7061(26)00230-8. [Epub ahead of print]

Citrate-functionalised hydroxyapatite mimics the microenvironment of bone metastases and demonstrates the role of citrate in prostate cancer colonization of bone.

Alessandro Pasquarelli, Elena Cavassi, Letizia Bucchi, Elisa Boanini, Gemma Di Pompo, Maria Veronica Lipreri, Francesca Perut, Yasmine Bouidida, Pierre Sonveaux, Katia Rubini, Matteo Montesissa, Rossella Santonocito, Nicola Baldini, Sofia Avnet.

  Prostate cancer (PCa) is the second leading cause of cancer-related mortality in men, with bone representing the predominant metastatic site. Progress in treating bone metastatic disease is hindered by lack of preclinical models that faithfully recapitulate the bone microenvironment while reducing animal use. Biomaterial-based platforms offer a powerful alternative, enabling controlled reconstruction of bone composition, metabolic cues, and tumour-matrix interactions. A defining feature of PCa progression is citrate-centred metabolic reprogramming. While healthy prostate epithelial cells accumulate and secrete citrate, aggressive PCa cells import and oxidise it to sustain growth. Given the citrate-rich nature of prostate tissue and bone, we hypothesised that bone-derived citrate may be exploited by metastatic PCa cells to support bone colonisation. We developed a bone-mimetic platform by functionalising hydroxyapatite nanocrystals with citrate (HA-Nc-Cit) and incorporating them into collagen-based 3D matrices within a microfluidic chip. HA-Nc-Cit were characterised and citrate release quantified. Metastatic PCa cells were analysed for migration, viability, clonogenicity, metabolic reprogramming, and citrate transporter expression. HA-Nc-Cit released physiologically relevant citrate levels. Citrate exposure enhanced migration of androgen-independent PC3 cells and, within collagen type I-enriched matrices, increased clonogenicity, upregulated plasma membrane citrate transporter, suppressed glycolysis, and promoted lactate fermentation and mitochondrial biogenesis, without affecting respiratory chain or lipid metabolism. Citrate buffering supported PC3 clonal survival under acidic stress mimicking tumour acidification. In conclusion, citrate-functionalised HA-Nc promotes bone tropism of aggressive PCa by enhancing migratory potential, modulating tumour metabolism, and buffering extracellular acidification, underscoring the value of biomaterial-based models for studying bone-tumour interactions and guiding therapeutic development. STATEMENT OF SIGNIFICANCE: PCa often spreads to bone, but current models fail to capture the complexity of bone environment, limiting progress in treatment development. In this study, we created a 3D bone-mimicking system by binding citrate, a key bone metabolite, to hydroxyapatite nanocrystals mimicking bone mineral and embedding them in collagen-based matrices. This platform shows how citrate not only fuels PCa cells but also buffers the acidic conditions they create, making bone more prone to tumour growth. Unlike traditional models, such biomaterial-based approach combines mineral chemistry, metabolism, and pH regulation in a controlled setting. This work introduces a tool to study bone-tumour interactions and guide future therapies for metastatic PCa.

Keywords:  3D microfluidic model; Bone metastasis; citrate; hydroxyapatite nanocrystals; prostate adenocarcinoma

DOI:  https://doi.org/10.1016/j.actbio.2026.04.019