bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2026–04–26
sixteen papers selected by
Grigor Varuzhanyan, UCLA



  1. Discov Oncol. 2026 Apr 21.
       BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer mortality in men. Lamin B2 (LMNB2) has been implicated in various cancers, but its functional role and molecular mechanisms in PCa progression remain poorly characterized.
    METHODS: We analyzed LMNB2 expression and clinical associations using transcriptomic data from TCGA, GEO and PCaDB. Functional enrichment analysis identified related pathways. LMNB2 was knocked down in PCa cell lines (LNCaP and PC-3) and its effects on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were assessed. The Wnt/β-catenin pathway was investigated using agonist SKL2001. Subcutaneous xenograft models in nude mice were established for in vivo validation.
    RESULTS: The experimental findings demonstrate that reduced expression of LMNB2 substantially impairs cellular proliferation, tumor formation ability, and the epithelial-to-mesenchymal transition phenotype in prostate carcinoma cells by interfering with Wnt/β-catenin pathway activation. Furthermore, LMNB2 knockdown effectively suppressed tumor growth in mouse xenograft models. Notably, immunohistochemical evaluation of tumor tissues from xenografts revealed significantly higher LMNB2 protein levels that were associated with poor patient prognosis. These comprehensive results establish LMNB2 as a critical oncogenic driver that promotes both primary tumor development and metastatic spread in prostate adenocarcinoma.
    CONCLUSIONS: LMNB2 promotes prostate cancer progression by activating the Wnt/β-catenin signaling pathway and inducing EMT, highlighting its potential as a prognostic biomarker and therapeutic target.
    Keywords:  Epithelial-mesenchymal transition; LMNB2; Prostate cancer; Wnt/β-catenin signaling pathway
    DOI:  https://doi.org/10.1007/s12672-026-05015-y
  2. Mol Cancer Ther. 2026 Apr 22.
      Advanced and treatment-refractory prostate cancer, including castration-resistant disease, require new therapeutic strategies. TRPM4, a calcium-activated monovalent cation channel, regulates cell volume and promotes cancer progression. Acetalax induces oncosis-like death in TRPM4-positive triple-negative breast cancers, suggesting a TRPM4-dependent vulnerability. Here, we investigated whether TRPM4 expression defines Acetalax sensitivity in prostate cancer. We compared Acetalax sensitivity in TRPM4-high and -low prostate cancer cell lines, including androgen-dependent (LNCaP), castration-resistant (22Rv1), and androgen-independent (PC3, DU145) models. We evaluated TRPM4 dynamics and oncosis-associated phenotypes by Western blotting and immunofluorescence. Resistant clones were developed through continuous drug exposure. TRPM4 expression in patient samples was analyzed using prostate cancer tissue microarray and The Cancer Genome Atlas (TCGA). Transcriptional changes following TRPM4 loss were examined by RNA sequencing (RNA-seq). Antitumor activity and tolerability were evaluated in TRPM4-positive patient-derived xenograft (PDX) models. TRPM4-high cells (PC3, LNCaP and 22Rv1) underwent oncosis-like swelling and TRPM4 degradation upon Acetalax exposure, whereas TRPM4-low cell and resistant clones (DU145 and chronic exposure cells) remained insensitive and lacked TRPM4 expression. RNA-seq revealed transcriptomic remodeling associated with TRPM4 loss. TRPM4 was significantly elevated in tumors versus normal tissues and was unchanged across stages or Gleason scores. In TRPM4-positive PDX models, Acetalax (300 mg/kg) significantly suppressed tumor growth without body-weight loss, indicating antitumor efficacy without overt toxicity. TRPM4 is a mechanistic driver and predictive biomarker of Acetalax response in prostate cancer, supporting TRPM4-dependent targeting and providing a rationale for the clinical development of Acetalax for TRPM4-expressing and treatment-refractory prostate cancer.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-26-0011
  3. Neoplasia. 2026 Apr 17. pii: S1476-5586(26)00036-9. [Epub ahead of print]77 101307
      Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype that emerges through lineage plasticity following androgen receptor pathway inhibition. Although MYC family oncogenes are central to prostate cancer progression, the role of MYCL (L-MYC) in NEPC has remained poorly defined. Here, we show that MYCL is selectively and robustly upregulated in NEPC patient samples and experimental models, whereas MYC is concurrently suppressed and MYCN remains low, revealing a lineage-associated MYC family switch. MYCL expression strongly correlates with the neuroendocrine lineage regulators ASCL1 and INSM1 and inversely with adenocarcinoma-associated genes. Functionally, MYCL overexpression suppresses androgen receptor signaling, induces neuroendocrine-like transcriptional reprogramming, and remodels cytoskeletal and adhesion pathways associated with cellular plasticity, whereas MYCL knockdown disrupts neuroendocrine lineage identity and restores adenocarcinoma-associated gene expression, including MYC. Mechanistically, MYC suppression is associated with transcriptional regulation by ASCL1, while MYCL upregulation appears to occur within a permissive epigenetic landscape rather than through genomic amplification. Together, these findings identify MYCL as a lineage-specific regulator that drives and maintains neuroendocrine identity and define a MYC family regulatory switch in which MYCL replaces MYC to stabilize neuroendocrine lineage programs in advanced prostate cancer.
    Keywords:  MYCL; Neuroendocrine; Prostate cancer
    DOI:  https://doi.org/10.1016/j.neo.2026.101307
  4. Genes Dis. 2026 Jul;13(4): 101903
      The androgen receptor (AR) signaling axis is regarded as the key driver of prostate cancer (PCa). Besides acting as a well-characterized transactivator of diverse targets, accumulating evidence suggests that AR can also function as a transrepressor. However, AR-repressed targets and their significance in PCa and castration-resistant PCa (CRPC) remain poorly understood. Among multiple mechanisms, intratumoral androgen biosynthesis is regarded as an important factor responsible for persistent AR signaling in CRPC. Previously, we characterized that the nuclear receptor LRH-1 (NR5A2) plays a key role in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of multiple key steroidogenic enzymes. However, the transcriptional control of LRH-1 in PCa is still undefined. In this study, we show that androgen-activated AR could suppress, whereas antiandrogen-suppressed AR could up-regulate the LRH-1 expression in PCa cells. Furthermore, our genomics analysis showed that the transcriptional repression of NR5A2 by ligand-activated AR was mediated through the induction of a distinct androgen-dependent chromatin looping formed within the topologically associated domain of NR5A2 via direct binding of AR to the regulatory elements of NR5A2. Our present study demonstrates the significance of decreased androgen levels in androgen-deprivation therapy, resulting in the relief or up-regulation of LRH-1 toward intratumoral androgen biosynthesis in CRPC.
    Keywords:  Androgen receptor; Castration-resistance; Chromatin looping; LRH-1; Prostate cancer
    DOI:  https://doi.org/10.1016/j.gendis.2025.101903
  5. Transl Oncol. 2026 Apr 17. pii: S1936-5233(26)00080-X. [Epub ahead of print]68 102743
      Prostate cancer (PCa), a common malignancy, is a leading cause of cancer-related deaths among men. Advances in high-throughput technologies have led to the identification of various genetic alterations, including amplifications, deletions, mutations, gene fusions, and aberrant gene expressions, associated with PCa initiation and progression. Identifying key drivers of tumor progression and their underlying signaling pathways contributes to early diagnosis and therapeutic targeting. Here, we showed that thyroid hormone receptor-interacting protein 13 (TRIP13), a member of the AAA-ATPase family is overexpressed in PCa. Additionally, we observed amplification of the TRIP13 locus in a small subset of PCa samples. Functional studies demonstrated that TRIP13 knockdown in PCa cells reduced their proliferation and invasion. Furthermore, ectopic overexpression of TRIP13 in prostate epithelial cells (RWPE-1) resulted in enhanced cell invasion. Additionally, pharmacologic inhibition of TRIP13 by the small molecule inhibitor DCZ0415 suppressed PCa cell proliferation, induced apoptosis, modulated markers of the epithelial-mesenchymal transition (EMT), and inhibited tumor growth. Overall, these findings highlight a functional role for TRIP13 in PCa progression and demonstrate its potential as a therapeutic target in TRIP13-overexpressing PCa.
    Keywords:  Apoptosis; Invasion; Metastasis; Prostate Cancer; TRIP13
    DOI:  https://doi.org/10.1016/j.tranon.2026.102743
  6. Biochem Biophys Res Commun. 2026 Apr 18. pii: S0006-291X(26)00572-3. [Epub ahead of print]819 153808
      Prostate cancer (PCa) is primarily driven by androgen receptor (AR) signaling, where a potent form of androgen, such as dihydrotestosterone (DHT), binds with AR to promote tumor cell proliferation and survival. Somatic mutations in AR gene are recognized as key predictive indicators of therapeutic resistance to anti-androgen therapy in advanced stages of PCa. To enable minimally invasive detection of these alterations, we developed an ultrasensitive digital droplet PCR (ddPCR) assay capable of quantifying absolute copies of AR mutant alleles relative to wild-type AR using cell-free circulating DNA isolated from the patient's plasma. This approach demonstrated a reliable surveillance of hotspot AR mutation that emerges in response to drug treatment. Furthermore, quantitative plasma cell-free DNA (cfDNA) levels provide a dynamic proxy for tumor burden, with sharp post-therapy declines serving as a real-time indicator of treatment efficacy. These findings highlight the prototype standardization of cfDNA-based AR mutation assay in Indian PCa patients, establishing a framework to enable personalized treatment strategies, real-time disease monitoring, and therapeutic response.
    Keywords:  Androgen receptor; Cell-free DNA; Digital droplet PCR; Drug resistance biomarker; Hotspot mutations; Liquid biopsy
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153808
  7. Sci Rep. 2026 Apr 22.
      
    Keywords:  M2 macrophage polarization; Prostate cancer; STAT3 signaling pathway; Tumor microenvironment; tRNA-derived fragment tRF-3017b
    DOI:  https://doi.org/10.1038/s41598-026-48277-w
  8. Am J Cancer Res. 2026 ;16(3): 1081-1101
      Prostate cancer (PCa) is one of the most common malignant tumors in males. Characterized by an insidious onset, the majority of patients are diagnosed at an advanced stage upon initial presentation. Therefore, it is particularly important to find the potential biomarkers for early diagnosis of PCa. The expression and stability of circKLK3-25 in PCa cells were assessed by qRT-PCR and Actinomycin D testing. Cell Counting Kit-8 assay, EdU staining, scratch-wound assay and transwell experiments were used to make clear the influences of circKLK3-25 on the progression of PCa cells. Target miRNAs of circKLK3-25 was analyzed by bioinformatics. Western blot determined the expressions of proteins associated with the JNK/ERK pathway and epithelial-mesenchymal transition (EMT). Finally, subcutaneous xenograft tumor models were formed in nude mice to uncover the interference of circKLK3-25 with PCa progression in vivo. The results showed that circKLK3-25 was significantly highly expressed in PCa cells with good stability. Overexpression circKLK3-25 propelled PCa cells to proliferate, invade, migrate, and EMT process; conversely, silencing circKLK3-25 impaired the malignant biological properties of such cells. Overexpression circKLK3-25 led to upregulation of JNK/ERK signaling pathway-related proteins, while silencing circKLK3-25 lead to the opposite trend. Pathway inhibitors attenuated the pro-oncogenic effects of overexpression of circKLK3-25. circKLK3-25 was a sponge for miR-874-3p, and overexpression of miR-874-3p suppressed the PCa malignant phenotype and EMT. Besides, in vivo experiments demonstrated that overexpression circKLK3-25 activated the JNK/ERK signaling pathway and promoted tumor growth, and silencing circKLK3-25 did the opposite. In conclusion, circKLK3-25 is notably overexpressed in PCa cells and promotes PCa malignant progression through activating JNK/ERK signal pathway.
    Keywords:  JNK/ERK pathway; Prostate cancer; circKLK3-25; epithelial-mesenchymal transition; proliferation
    DOI:  https://doi.org/10.62347/GVSL6170
  9. Nanomedicine. 2026 Apr 22. pii: S1549-9634(26)00049-3. [Epub ahead of print] 102948
      This study presents MSNCHDT@DTX, mesoporous silica nanoparticles (MSN) functionalized with choline and diethylenetriaminepentaacetic acid (DTPA), designed as a theranostic agent integrating targeting, imaging, and therapy. Docetaxel (DTX) use in prostate cancer is limited by poor water solubility and systemic toxicity. Exploiting elevated choline uptake in PC-3 cells, MSN were covalently functionalized with choline and DTPA, with DTX subsequently encapsulated within the mesoporous framework. Structure elucidating techniques confirmed successful synthesis, while comprehensive physicochemical characterization validated the grafting of choline and DTPA onto the nanoparticle surface and confirmed drug encapsulation. The system demonstrated stability under physiological conditions and high selectivity for PC-3 human prostate cancer cells, achieving ~88% increased cellular uptake. Cytotoxic activity surpassed both non-targeted nanoparticles and free drug, with an IC50 of 20 μg/mL at 48 h. By selectively targeting cancerous cells while sparing healthy tissue, MSNCHDT@DTX represents a promising advancement in prostate cancer theranostics.
    Keywords:  Choline targeting; Docetaxel; Mesoporous silica nanoparticles; Prostate cancer; Theranostics
    DOI:  https://doi.org/10.1016/j.nano.2026.102948
  10. Curr Pharm Des. 2026 Apr 14.
      Androgen receptor (AR) signalling is central to both normal prostate physiology and prostate cancer (PCa) progression. Its activity is tightly regulated by localization, transcriptional control, and post-translational modifications. Among these, poly (ADP-ribose) polymerase (PARP) mediated ADP-ribosylation has emerged as a key regulator. Multisite cysteine mono-ADP-ribosylation of AR by PARP7 modulates its function. Molecular recognition of ADP-ribosyl-cysteine by PARP9/DTX3L influences AR-driven gene expression. Importantly, defects in homologous recombination repair (HRR) genes have made PARP inhibitors (PARPi) an effective treatment for BRCA (Breast cancer susceptibility genes 1 and 2)-mutated metastatic castration-resistant prostate cancer (mCRPC). Clinical trials such as TALAPRO-2 show that combining PARPi with AR signalling inhibitors can be effective; however, their benefit in tumours without HRR mutations remains unclear. PARP enzymes regulate AR via MARylation and PARylation, with inhibitors such as Olaparib, which disrupts AR-PARP crosstalk. In this review, we present current knowledge on the interplay between ADP-ribosylation and AR signalling in prostate cancer, emphasizing the roles of distinct PARP enzymes in shaping AR activity and therapeutic response. Herein, we focus on the combined contributions of MARylation and PARylation to prostate tumorigenesis. We also discuss how this complex regulatory network may contribute to the development of advanced prostate cancer therapies in the future. This could improve PARP inhibitor and AR signalling inhibitor combinations and allow more patients to benefit from them.
    Keywords:  ADP-ribosylation; Androgen receptor (AR); MARylation and PARylation; PARP enzymes; PARP inhibitors; prostate cancer
    DOI:  https://doi.org/10.2174/0113816128442440260321120151
  11. Commun Biol. 2026 Apr 20.
      Zinc, an essential trace element for healthy prostate, which dramatically decreases during prostate tumorigenesis. Targeting the key zinc signaling will be a valuable strategy for PCa therapy. However, the underlying mechanisms are poorly understood. Here, we show that zinc is significantly decreased in prostate cancer (PCa), especially in metastatic PCa. Screening reveals that a zinc transporter Zip7 was upregulated in metastatic PCa and related to poor progression. Zip7 silencing inhibits PCa cell migration and invasion in vitro and bone-metastasis in vivo. Mechanistically, we identify that Zip7 mainly interacts with MAZ in cytoplasm to facilitate MAZ nuclear import and nuclear MAZ was up-regulated in metastatic prostate cancer tissues and positively associated with Zip7 expression, which promotes PCa bone metastasis. Furthermore, our RNA-seq studies reveal that Zip7 facilitates MAZ nuclear import to promote MYBL2 transcription. Strikingly, we show in intraarterial injected-bone metastasis xenograft model that targeting Zip7 by its inhibitor markedly suppressed PCa bone metastasis. Collectively, our findings identify Zip7 is an important regulator of PCa metastasis and targeting Zinc-dependent Zip7-MAZ-MYBL2 could be a valuable strategy to ameliorate advanced PCa metastasis.
    DOI:  https://doi.org/10.1038/s42003-026-10074-6
  12. Int J Cancer. 2026 Apr 22.
      Although immunotherapy has transformed the treatment of several genitourinary malignancies, its role in prostate cancer remains limited. Combining immunotherapy with targeted therapies has emerged as a promising approach to enhance immune responses in prostate cancer. We aimed to systematically evaluate the efficacy and safety of immunotherapy combined with targeted therapy in the treatment of prostate cancer. We conducted a detailed literature search across Embase, Scopus, PubMed, Web of Science, and the Cochrane Library to include clinical trials enrolling adults with histologically confirmed prostate cancer treated with a combination of targeted therapy and immunotherapy. A systematic review and meta-analysis were performed according to a registered protocol. A total of 21 studies from 19 clinical trials, encompassing 5702 participants, were included. The studies evaluated 12 unique therapeutic combinations involving six targeted agents and four immunotherapies. Seven trials compared combination therapy with monotherapy. Pooled analyses showed that combination therapy significantly improved disease control rate (RR = 1.42), complete response (RR = 2.56), and partial response (RR = 2.13), albeit with a higher incidence of adverse events. In single-arm studies, the pooled median progression-free survival was 5.14 months, and median overall survival was 16.79 months. The androgen receptor signaling inhibitor subgroup exhibited longer survival than the PARP inhibitor subgroup. Combination immunotherapy and targeted therapy demonstrate superior efficacy over monotherapy in prostate cancer but increase the risk of toxicity. These promising results warrant further validation in large-scale, well-designed randomized trials.
    Keywords:  immunotherapy; meta‐analysis; prostate cancer; synergistic; target therapy
    DOI:  https://doi.org/10.1002/ijc.70512
  13. Eur J Med Chem. 2026 Apr 20. pii: S0223-5234(26)00307-7. [Epub ahead of print]312 118862
      Prostate cancer (PCa) is one of the most prevalent malignancies in males. While androgen receptor (AR) antagonists play a crucial role in PCa therapy, their efficacy is often limited by resistance arising from AR mutations. Here, we identified S-94, corresponding to the S-enantiomer of compound 94, as a novel AR antagonist with marked selectivity for the T878A-mutant AR. In vitro, S-94 inhibited AR transcriptional activity (IC50 = 0.38 μM) and suppressed cell proliferation (IC50 = 10.32 μM) in LNCaP cells harboring the T878A-mutant AR, while exhibiting lower cytotoxicity toward non-cancerous cells. In vivo, S-94 (20 mg/kg, i.p.) inhibited tumor growth in an LNCaP xenograft model. Mechanistic studies showed that S-94 selectively targeted the T878A-mutant AR, exhibiting 50-fold greater potency against ART878A (IC50 = 0.49 μM) than against wild-type AR (IC50 = 27.18 μM). Moreover, S-94 antagonized several clinically relevant T878A-associated AR mutants, including ARF877L/T878A and ARH875Y/T878A, and displayed high selectivity over GR, MR, and PR. In summary, the study suggests that S-94 targets the T878A-mutant AR as a selective AR antagonist with limited impact on the physiological wild-type AR, and effectively antagonizes clinically relevant T878A-associated AR mutants. These properties highlight S-94 as a promising and potentially safer lead compound for the treatment of prostate cancers harboring T878A-associated AR mutations.
    Keywords:  Androgen receptor antagonist; Drug resistance; Prostate cancer; T878A mutation; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ejmech.2026.118862
  14. Front Oncol. 2026 ;16 1733046
      Predicting prostate cancer (PCa) recurrence after radical treatment is crucial for personalised adjuvant therapy. This study aimed to compare different algorithms in order to select the best model for predicting recurrence. Therefore, a retrospective cohort analysis was conducted on 72 patients with radical prostate cancer, including 39 patients with biochemical recurrence and 33 patients without recurrence. We extracted features from imaging data, construct and evaluate 10 machine learning models and 8 deep learning models. Model performance was assessed using the area under the curve (AUC), accuracy, sensitivity, specificity, precision, 10-fold cross-validation AUC, and F1-score. In addition, the feature importance was analysed. Among all models, the MLP-Mixed-Act model exhibited superior performance in all evaluation indicators (AUC = 0.910, accuracy =0.819, sensitivity =0.744, specificity =0.909, precision =0.912, F1 = 0.817), thereby indicating its strong predictive ability and clinical application potential. This study provides a theoretical basis for the development of preventive and non-invasive recurrence prediction tools. Especially in the context of valuing the tumor microenvironment, accurate recurrence prediction can effectively help select immunotherapy strategies, improve treatment efficacy and prognosis, and support for personalized treatment of PCa.
    Keywords:  deep learning; positron emission tomography/computed tomography; prostate cancer; radiomics; recurrence prediction
    DOI:  https://doi.org/10.3389/fonc.2026.1733046
  15. Proc Natl Acad Sci U S A. 2026 Apr 28. 123(17): e2523965123
      Chromosomal instability (CIN) is a prevalent form of genomic instability in prostate cancer (PCa). However, its molecular mechanisms remain inadequately understood. This study demonstrates that reduced expression of UFM1-ligase 1 (UFL1) is commonly observed in PCa and correlates with elevated CIN rates. UFL1 deficiency results in severe mitotic defects, errors in chromosome segregation, and aneuploidy, thereby promoting malignant transformation. Mechanistically, UFL1 interacts with RNF20 and catalyzes its UFMylation, which enhances RNF20 binding to CEP192, facilitating its centrosomal localization and supporting mitotic spindle assembly. Additionally, downregulation of the microphthalmia-associated transcription factor (MITF) exacerbates PCa aggressiveness by suppressing UFL1 expression. These findings identify the MITF-UFL1-RNF20 axis as a critical regulator of spindle integrity and a potential therapeutic target in PCa.
    Keywords:  RNF20; UFL1; chromosomal instability; prostate cancer
    DOI:  https://doi.org/10.1073/pnas.2523965123