bims-meproc 2026-06-14 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–06–14
twenty papers selected by
Grigor Varuzhanyan, UCLA

The role of lysophosphatidic acid metabolism in castration-resistant prostate cancer progression.
Glutamyl-tRNA synthetase 2 regulates mitochondrial biogenesis and reactive oxygen species homeostasis mediatingenzalutamide resistance by targeting striatin 4 in prostate cancer cells.
A Fully Human Engineered Bone Niche With Endogenous Osteoclastogenesis Reveals Osteoclast-Dependent Osteomimicry in Prostate Cancer Cells.
Androgen receptor reactivation in castration-resistant prostate cancer: mechanisms, epigenetic adaptation, and therapeutic vulnerabilities.
A Metabolic-Related Gene Signature for Predicting Biochemical Recurrence After Radical Prostatectomy: An Integrative Analysis and Targeted Therapeutic Validation.
Co-targeting EGFR and SUCLG2 disrupts a nuclear transcriptional program driving neuroendocrine differentiation and TKI resistance in castration-resistant prostate cancer.
Letter: Testosterone Does Not Drive Prostate Cancer: Presenting the New Framework of Androgen Adequacy Versus Inadequacy.
Integrated multi-omics profiling uncovers the epigenetic, transcriptional, and metabolic landscape of prostate cancer progression.
Nonsteroidal 18F-Labeled PET Tracer for Imaging Androgen Receptors.
CDO1 is a new biomarker to discriminate aggressive forms of prostate cancer.
Histone chaperone HIRA restrains ferroptosis susceptibility through epigenetic control of iron metabolism in prostate cancer.
Epigenetic and oncogenic inhibitors converge to drive a metabolic catastrophe in castration-resistant prostate cancer.
Cold atmospheric plasma selectively induces toxicity of prostate cancer cells associated with oxidative stress.
Targeting the ELF1/EGFR/ERK positive feedback loop overcomes resistance to androgen receptor inhibition in AR-Vs positive prostate cancer.
Prognostic alternative mRNA splicing signature and immune infiltration in prostate cancer.
A Novel Drug Candidate that Selectively Targets the Critical Androgen Receptor-ELK1 Growth Axis in Advanced and Drug-Resistant Prostate Cancer.
Single-Cell and Spatial Transcriptomics Uncover Immune Dynamics and Cellular Heterogeneity in Benign Prostatic Hyperplasia and Prostate Cancer Transition.
MCCC2 stabilizes LTBP1 via suppressing SMURF1-dependent ubiquitination to drive bone metastasis in prostate cancer.
Integrated Single-Cell RNA-Seq and Machine Learning to Construct an EMT Infiltration Scoring Model for Prostate Cancer.
Metformin and Flutamide Combination Therapy's Efficacy and Safety in Prostate Cancer Cell Lines.

Front Oncol. 2026 ;16 1842091

The role of lysophosphatidic acid metabolism in castration-resistant prostate cancer progression.

Jinpeng Feng, Jiale Liu, Yi He.

  Prostate cancer (PCa) is a leading malignancy in men, with mortality primarily attributed to progression to castration-resistant prostate cancer (CRPC). Although androgen deprivation therapy (ADT) initially demonstrates efficacy, most advanced patients eventually develop CRPC-a stage characterized by limited treatment options and poor prognosis. Elucidating the molecular mechanisms underlying CRPC transformation therefore represents a research priority. Tumor metabolic reprogramming has emerged as a hallmark of cancer, and among various metabolic pathways, lysophosphatidic acid (LPA)-a bioactive lipid mediator-has been increasingly implicated in PCa progression, particularly CRPC transformation. This review systematically examines LPA metabolic sources and signal transduction mechanisms and explores how LPA promotes CRPC progression through driving proliferation, survival, invasion, therapy resistance, and tumor microenvironment remodeling. Finally, we discuss the potential and challenges of targeting the LPA signaling pathway as a novel therapeutic strategy for CRPC.

Keywords:  castration resistance; lysophosphatidic acid; metabolic reprogramming; prostate cancer; targeted therapy

DOI:  https://doi.org/10.3389/fonc.2026.1842091
J Physiol Pharmacol. 2026 Apr;77(2): 249-264

Glutamyl-tRNA synthetase 2 regulates mitochondrial biogenesis and reactive oxygen species homeostasis mediatingenzalutamide resistance by targeting striatin 4 in prostate cancer cells.

B Q Wang, X Wang, W Liu, L Jin.

  Although enzalutamide (ENZA) has improved the overall survival of patients with metastatic prostate cancer, ENZA resistance (ENZA-resistant) inevitably develops, largely limiting its efficacy. Alternative oncogenic pathways may bypass androgen receptor (AR) signaling to promote ENZA-resistant. Glutamyl-tRNA synthetase 2 (EARS2) is involved in mitochondrial biogenesis and is associated with cancer, but its action mechanism in prostate cancer (PCa) is not well defined. EARS2 expression was detected in primary PCa and castrate-resistant prostate cancer samples, ENZA-resistant cell lines, and ENZA-resistant xenograft models, and the prognostic relationship of EARS2 in patients with PCa was analyzed. In AR-sensitive LNCaP cells, changes in EARS2 expression were explored before and after stimulation with dihydrotestosterone (DHT) or bicalutamide. AR was knocked down in AR-positive LNCaP and C4-2B cells to explore the relationship between EARS2 and AR. The effect of EARS2 on PCa cells was further explored. ENZA-resistant xenograft model was built to explore the effect of EARS2 on tumorigenesis in vivo. EARS2 was knocked down in C4-2B-ENZA-resistant, and the relationship between EARS2 and mitochondrial biogenesis and reactive oxygen species (ROS) homeostasis was investigated in PCa cells. Finally, the relationship between EARS2 and striatin 4 (STRN4) was explored. EARS2 expression was elevated in PCa and correlated with ENZA-resistant, and high EARS2 expression was associated with poorer patient prognosis. In androgen-sensitive LNCaP cells, DHT inhibited EARS2 expression, and silencing AR increased EARS2 expression. Suppressing EARS2 inhibited the proliferation, colony formation, migration and invasion ability, down-regulated the IC50 of ENZA in ENZA-resistant cells, and promoted apoptosis. Stable EARS2 downregulation in C4-2B-ENZA-resistant significantly inhibited tumor growth. Suppressing EARS2 in ENZA-resistant cells may lead to increased mitochondrial biogenesis and ROS generation. Mechanistically, EARS2 inhibited mitochondrial biogenesis and ROS generation in PCa cells by targeting STRN4. EARS2 targets STRN4 to modulate mitochondrial biogenesis and ROS homeostasis mediating ENZA-resistant.

Keywords:  androgen receptor; enzalutamide resistance; glutamyl-tRNA synthetase 2; homeostasis; mitochondrial biogenesis; prostate cancer; reactive oxygen species; striatin 4

DOI:  https://doi.org/10.26402/jpp.2026.2.07
Adv Healthc Mater. 2026 Jun 11. e05893

A Fully Human Engineered Bone Niche With Endogenous Osteoclastogenesis Reveals Osteoclast-Dependent Osteomimicry in Prostate Cancer Cells.

Andrea Mazzoleni, Robin Dolgos, Thomas Menter, Boris Dasen, Arnaud Scherberich, Clémentine Le Magnen, Manuele G Muraro, Ivan Martin.

  Bone is the predominant site of metastasis in advanced prostate cancer (PCa), yet the mechanisms governing tumor-bone interactions remain incompletely understood, thanks in part to the scarcity of relevant models. The role played by osteoclasts in such interactions is especially obscure. A modular human three-dimensional (3D) in vitro bone niche model was developedThe model integrates osteoblasts and osteoclasts within a mineralized scaffold, recreating an endosteal-like microenvironment for co-culture with PCa cell lines and patient-derived organoids (PDOs). The engineered construct maintains osteoblastic differentiation and supports osteoclastogenesis, confirmed by lineage markers including osteocalcin, osteopontin (OPN), and tartrate-resistant acid phosphatase (TRAP). Co-culture with PCa cells downregulates osteoblast- and osteoclast-associated genes (IBSP, OPN, TRAP) in bone cells, suggesting tumor-mediated suppression of bone remodeling. Conversely, co-cultured PCa cells exhibit niche-dependent osteomimicry, characterized by upregulation of osteoblastic (SPARC, BGLAP) and osteoclastic (TRAP) markers and strongly regulated by the presence of osteoclasts. The platform also supports engraftment and proliferation of PDOs without exogenous PCa-specific growth factors, underscoring its translational relevance. This osteoblastic-osteoclastic niche model provides a human system that captures PCa-bone cell interactions in a clinically relevant context, with potential utility for mechanistic and translational studies.

Keywords:  3D in vitro model; bone metastatic niche; osteomimicry; prostate cancer bone metastasis; tumor–bone interactions

DOI:  https://doi.org/10.1002/adhm.202505893
Front Oncol. 2026 ;16 1837998

Androgen receptor reactivation in castration-resistant prostate cancer: mechanisms, epigenetic adaptation, and therapeutic vulnerabilities.

Juntao Guo, Ke Wu, Zheng Ma, Shuai Guo, Fei Wang, Lingxiang Lu.

  Castration-resistant prostate cancer (CRPC) remains a difficult clinical problem, although androgen deprivation therapy and next-generation androgen receptor (AR) pathway inhibitors have greatly improved patient treatment. CRPC is not simply an androgen-independent disease. In many cases, tumor cells still depend on persistent or restored AR signaling under castrate conditions. AR reactivation is driven by several overlapping mechanisms, including AR amplification, AR overexpression, ligand-binding domain mutations, AR splice variants, intratumoral androgen synthesis, bypass signaling, and altered AR co-regulators. The AR axis is also connected with DNA damage repair. For example, PARP-1 can support both DNA repair and AR-driven transcription, which provides a rationale for combining AR-targeted therapy with PARP inhibition in selected patients. Epigenetic adaptation is another key layer in this process. Changes in chromatin accessibility, AR cistrome redistribution, pioneer factors, enhancer activity, and chromatin-modifying cofactors can reshape AR-dependent transcription. These changes help tumor cells maintain AR signaling and also promote heterogeneity, lineage plasticity, and more aggressive phenotypes. Recent single-cell transcriptomic and epigenomic studies further show that CRPC contains diverse resistant cell states, which may change during treatment. Importantly, these resistance mechanisms may also create therapeutic opportunities. Current and emerging strategies include AR degraders, AR N-terminal domain inhibitors, inhibitors of steroidogenesis and bypass pathways, PARP inhibitors, and epigenetic therapies targeting EZH2, BET proteins, p300/CBP, LSD1, or HDACs. Biomarker-guided treatment, including AR variants, DNA repair defects, ctDNA profiles, and chromatin states, may help select better therapies for CRPC patients.

Keywords:  AR splicevariants; androgen receptor reactivation; castration-resistant prostate cancer; epigenetic adaptation; precision therapy; therapeutic vulnerabilities; transcriptional reprogramming

DOI:  https://doi.org/10.3389/fonc.2026.1837998
Int J Mol Sci. 2026 May 26. pii: 4797. [Epub ahead of print]27(11):

A Metabolic-Related Gene Signature for Predicting Biochemical Recurrence After Radical Prostatectomy: An Integrative Analysis and Targeted Therapeutic Validation.

Wankun Wang, Xiujuan Hong, Xiaoqi Wang, Ganpei Jiao, Hongjie Cai, Junxiang Zhao, Zhibing Wu, Jun Chen.

  Biochemical recurrence (BCR) after radical prostatectomy (RP) remains a major clinical challenge. Although metabolic reprogramming drives prostate cancer (PCa) progression, its predictive value for BCR and its interplay with the tumor immune microenvironment (TIME) remain incompletely understood. By integrating weighted gene co-expression network analysis (WGCNA) with machine learning, we identified four metabolic-related hub genes (GDPD1, PLA2G7, PTGDS, and SRD5A2) and developed an XGBoost-Cox model that accurately stratified BCR risk (training 5-year AUC: 0.858; validation 5-year AUC: 0.745). SHAP analysis enhanced the model's interpretability, while immunohistochemistry (IHC) validated differential protein expression of these targets across 32 clinical specimens. Furthermore, immune profiling demonstrated that these genes are closely linked to M2 macrophage-mediated immunosuppression and altered T-cell infiltration. To translate these biomarkers into therapeutic targets, we employed in silico screening, molecular docking, and molecular dynamics simulations, identifying (-)-epigallocatechin gallate (EGCG) as a promising multi-target candidate. Subsequent in vitro assays confirmed that EGCG binds stably to GDPD1, PTGDS, and SRD5A2, effectively suppressing malignant PCa phenotypes and prostate-specific antigen (PSA) secretion. In summary, we established a robust and interpretable model for predicting BCR after RP, and our in vitro validation suggests that EGCG holds promise as a therapeutic agent to delay PCa progression.

Keywords:  biochemical recurrence; immune infiltration; machine learning; metabolic reprogramming; molecular docking; prognostic model; prostate cancer

DOI:  https://doi.org/10.3390/ijms27114797
Cell Commun Signal. 2026 Jun 08.

Co-targeting EGFR and SUCLG2 disrupts a nuclear transcriptional program driving neuroendocrine differentiation and TKI resistance in castration-resistant prostate cancer.

Wei-Yu Chen, Kuan-Hua Huang, Gagan Kajla, Yu-Ching Wen, Ming-Kun Liu, Yu Ching Fan, Phan Vu Thuy Dung, Hsiu-Lien Yeh, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Cheng-Sheng Chen, Jiaoti Huang, Himisha Beltran, Yen-Nien Liu.

Neuroendocrine prostate cancer (NEPC) is a lethal, treatment-resistant subtype that arises through lineage transdifferentiation from castration-resistant prostate cancer (CRPC) under selective pressure from androgen deprivation therapy. Although EGFR tyrosine kinase inhibitors (TKIs) represent a rational therapeutic strategy, their clinical efficacy remains limited, and the underlying resistance mechanisms are poorly defined. Through integrated molecular and functional analyses, we identified the mitochondrial succinyl-CoA ligase subunit SUCLG2 as a critical driver of neuroendocrine differentiation and EGFR-TKI resistance. EGF stimulation induced SUCLG2 nuclear translocation, where it formed a complex with phosphorylated EGFR and co-activated VEGFA transcription through co-occupancy of the VEGFA promoter to drive neuroendocrine gene programs. SUCLG2 overexpression conferred erlotinib resistance in vitro, whereas its depletion restored TKI sensitivity and impaired xenograft tumor growth, effects that were rescued by VEGFA reconstitution. Through in silico drug screening, we identified phenethyl isothiocyanate (PEITC) as a compound that reverses the SUCLG2-associated transcriptional signature and synergized with erlotinib to suppress patient-derived NEPC organoid growth and reduce xenograft tumor burden in vivo. In clinical specimens from CRPC patients and NEPC patient-derived xenografts, progressive nuclear co-accumulation of SUCLG2 and EGFR alongside elevated VEGFA expression correlated with disease advancement. Collectively, these findings define a non-canonical nuclear SUCLG2/EGFR/VEGFA signaling axis that mediates NEPC progression and therapeutic resistance, providing mechanistic rationale for combined SUCLG2 and EGFR inhibition as a strategy to overcome treatment resistance in this lethal malignancy.

DOI: https://doi.org/10.1186/s12964-026-02977-y
J Urol. 2026 Jul;216(1): 118-119

Letter: Testosterone Does Not Drive Prostate Cancer: Presenting the New Framework of Androgen Adequacy Versus Inadequacy.

Hector Rodrigo Gonzalez-Carranza, Luis Antonio Reyes-Vallejo.

DOI: https://doi.org/10.1097/JU.0000000000005007
BMC Cancer. 2026 Jun 08.

Integrated multi-omics profiling uncovers the epigenetic, transcriptional, and metabolic landscape of prostate cancer progression.

Christine Aaserød Pedersen, Maximilian Wess, Maria K Andersen, Elise Midtbust, Abhibhav Sharma, Thomas Fleischer, Morten Beck Rye, May-Britt Tessem.

  A comprehensive understanding of the underlying molecular mechanisms of prostate cancer is essential for the development of precise diagnostic biomarkers. In this study, we applied the unsupervised multi-omics factor analysis framework (MOFA) to integrate DNA methylation, gene expression, and metabolic profiles derived from the same individuals, aiming to characterize the biological landscape of normal, malignant, and aggressive prostate tissue. Our analysis identified distinct molecular pathways associated with aggressive disease, specifically those involved in zinc metabolism, cell cycle regulation, smooth muscle architecture, immune activation, and tissue morphology. Key metabolites within the TCA cycle, amino acid metabolism, and lipid pathways were central to these signatures. Furthermore, we observed a consistent co-enrichment of SP1 and CTCFL binding regions among factor-associated CpGs, suggesting a model of global epigenetic reprogramming. These findings indicate a novel interplay between Polycomb deregulation, CTCFL-mediated chromatin remodeling, and SP1-driven transcriptional activation in shaping the prostate cancer epigenome. Apart from immune activation, the identified molecular signatures were validated in the TCGA cohort and demonstrated significant predictive value for disease recurrence. Overall, these results underscore the power of multi-omics integration in providing a holistic understanding of prostate cancer biology and its potential for clinical translation into prognostic biomarkers.

Keywords:  DNA methylation ; Metabolomics; Multi-omics; Multi-omics factor analysis framework (MOFA); Prostate cancer; Transcriptomics

DOI:  https://doi.org/10.1186/s12885-026-16232-7
J Nucl Med. 2026 Jun 11. pii: jnumed.125.271531. [Epub ahead of print]

Nonsteroidal 18F-Labeled PET Tracer for Imaging Androgen Receptors.

Vilma I J Jallinoja, Joo Sun Mun, Alexandra Campanella, Aahna Sasson, Teja M Kalidindi, Giovanna Caxeiro, Darren R Veach, Serge Lyashchenko, Heiko Schöder, Naga Vara Kishore Pillarsetty.

  Androgen receptor (AR) signaling is the key driver of prostate cancer. Thus, standard-of-care treatments focus on androgen-deprivation therapy followed by AR signaling inhibitors. Even when initially responsive, patients eventually develop resistance to therapies targeting AR signaling, leading to disease progression. To study lesion-to-lesion AR occupancy, the radiofluorinated analog of the endogenous androgen [18F]16β-fluoro-5α-dihydrotestosterone ([18F]FDHT) has been investigated as a potential AR imaging agent. In the literature, [18F]FDHT demonstrates slow clearance from healthy tissue, poor plasma stability in vivo, and nonapplicability in mouse studies. To overcome these limitations, we explored nonsteroidal selective androgen receptor modulator (SARM)-based pharmacophores as potential PET tracers. Here, we describe the performance of a 18F-radiolabeled AR tracer, [18F]F-SARM3. Methods: [18F]F-SARM3 was synthesized via 1-step copper-catalyzed radiofluorination, and its AR affinity (half-maximal inhibitory concentration [IC50]) and biological activity (half-maximal effective concentration [EC50]) were studied in various prostate cancer cell lines. The tracer's stability in vitro was also evaluated. [18F]F-SARM3 was evaluated in LNCaP and 22Rv1 (AR-positive) tumor-bearing male mice to assess its AR specificity and clearance profile, and its performance was compared with that of [18F]FDHT. Results: [18F]F-SARM3 was synthesized with a radiochemical yield and purity of 2.7 ± 1.4% and 97.9 ± 2.3%, respectively. In in vitro cell-binding assays, [18F]F-SARM3 demonstrated high affinity for ARs, similar to that of dihydrotestosterone (IC50, 20.2 ± 14.6 nM vs. 9.6 ± 4.0 nM, respectively, in 22Rv1 cells). [18F]F-SARM3 functions as a partial AR agonist, with an EC50 of 15.0 ± 12.0 nM. Furthermore, [18F]F-SARM3 is highly stable in phosphate-buffered saline and mouse blood (98.5% ± 1.2% and 98.6% ± 1.5% intact, respectively). The tracer's in vivo specificity was confirmed with the observed uptake in tumors and prostate glands of castrated mice, where uptake was blockable. In vivo specificity was not observed with [18F]FDHT. Conclusion: We developed a first-in-class SARM-based AR tracer that displays high affinity and selectivity for AR in vitro and in vivo. This represents a suitable PET tracer to image AR status in rodent models and provides a strong rationale for clinical translation of [18F]F-SARM3 as a high-affinity AR agonist PET imaging agent.

Keywords:  18F; PET; androgen receptor; imaging; prostate cancer

DOI:  https://doi.org/10.2967/jnumed.125.271531
Oncogene. 2026 Jun 09.

CDO1 is a new biomarker to discriminate aggressive forms of prostate cancer.

Jeanne Gaspar Lopes, Angel Markovic, Cécile M Champy, Nicolas Aubourg, Jacques Rr Mathieu, Federica Alberti, Pascale Soyeux-Porte, Kadiatou Drame, Marine Louarn, Thibaud Jamet, Romain Huc, Alexandre de la Taille, Charles-Antoine Dutertre, Damien Destouches, Francis Vacherot, Virginie Firlej.

Worldwide, prostate cancer (PCa) ranks second in terms of incidence and eighth in terms of mortality. While most cancers remain silent after initial treatment, some tumors recur. At present, we are unable to predict which patients are at risk of recurrence. In order to determine this risk of recurrence as early as at the biopsy stage, and to enable better therapeutic management of patients, it is essential to identify new biomarkers. In this study, we have demonstrated that Cysteine Dioxygenase CDO1 could be a predictive marker in PCa progression. Transcriptomic analysis showed that CDO1 expression is significantly reduced in patients who have relapsed and lower CDO1 expression is associated with poorer survival outcomes. In PCa, CDO1 expression could be regulated by methylation and androgen signaling pathway. Furthermore, inhibition of CDO1 expression in VCaP prostate cancer cells led to increased cell migration and non-adherent growth. Finally, transcriptomic analysis of these cells with inhibited CDO1 expression demonstrates the complex role of CDO1 and its possible involvement in the mechanisms regulating endoplasmic reticulum stress and protein unfolding. Altogether, these results describe the loss of CDO1 as a marker of aggressiveness in PCa. Furthermore, the loss of CDO1 is thought to be responsible for tumor progression in vitro by acting on multiple signaling pathways.

DOI: https://doi.org/10.1038/s41388-026-03842-5
Sci China Life Sci. 2026 Jun 05.

Histone chaperone HIRA restrains ferroptosis susceptibility through epigenetic control of iron metabolism in prostate cancer.

Enlin Wang, Qilan Sun, Zhicheng Xu, Cong Huang, Yue Chen, Qingqing Wang, Siqi Liu, Xinrui Wang, Xiaohe Ren, Feng Sun, Sheng Tai, Mafei Xu.

  Ferroptosis, an iron-dependent form of immunogenic cell death (ICD), represents a promising anti-tumor therapeutic strategy via effectively activating immune responses. However, the regulatory mechanisms governing ferroptosis in prostate cancer remain poorly understood, significantly impeding the development of targeted therapeutic approaches. Through genome-wide CRISPR/Cas9 screening, we identified the histone chaperone HIRA as a novel ferroptosis suppressor in prostate cancer. Integrated analysis of public datasets and immunohistochemical validation demonstrated significant HIRA overexpression in prostate tumors, which was associated with diminished cytotoxic T lymphocyte infiltration and adverse clinical outcomes. Moreover, depletion of HIRA substantially enhanced ferroptosis susceptibility in vitro and in vivo, resulting in marked tumor growth inhibition. Mechanistic investigations revealed that HIRA orchestrates iron homeostasis through coordinated epigenetic regulation. While traditionally known to mediate H3.3 deposition in actively transcribed regions, we unexpectedly observed that HIRA depletion induced a widespread redistribution of H3.3 occupancy, with more regions gained than lost, suggesting compensatory H3.3 deposition dynamics. This redistribution coincided with increased chromatin accessibility and transcriptional regulation of iron metabolism genes, ultimately attenuating intracellular Fe2+ accumulation and ferroptosis resistance. Notably, HIRA depletion augmented CD4+ and CD8+ T cell infiltration and demonstrated synergistic efficacy with PD-1 immune checkpoint blockade in PCa models. Thus, our study establishes HIRA as an important epigenetic regulator of ferroptosis through iron metabolism modulation and nominates it as a promising therapeutic target for combination therapy in advanced prostate cancer.

Keywords:  H3.3; HIRA; ferroptosis; iron metabolism; prostate cancer

DOI:  https://doi.org/10.1007/s11427-025-3394-8
J Clin Invest. 2026 Jun 09. pii: e203835. [Epub ahead of print]

Epigenetic and oncogenic inhibitors converge to drive a metabolic catastrophe in castration-resistant prostate cancer.

Rhea Sahu, Miriam Enos, Swastika Sharma, Amy E Schade, Alycia Gardner, Akiko Yoshinaga, Alexandra Indeglia, Eleanor Minogue, Songhua Hu, Kiran Kurmi, Shakchhi Joshi, Daniel R Schmidt, Samkyu Yaffe, Van Tm Nguyen, Fang Xie, Steven P Balk, Matthew G Vander Heiden, Kristian Helin, Marcia C Haigis, Karen Cichowski.

  Men with advanced prostate cancer are typically treated with androgen deprivation therapy, but most ultimately develop resistance and incurable disease (e.g. castration-resistant prostate cancer (CRPC)). The majority of CRPCs overexpress the epigenetic enzyme EZH2 and harbor alterations in the PI3K pathway, providing two targetable pathways outside of AR. Here we show that EZH2 inhibitors synergize with PI3K, AKT, or mTORC1 inhibitors to kill CRPC in vitro and promote tumor regression in vivo. Strikingly, these agents trigger a catastrophic energy crisis by cooperatively suppressing glycolysis, the TCA cycle, and oxidative phosphorylation prior to cell death. EZH2 and PI3K pathway inhibitors achieve this by respectively inhibiting two key regulators of metabolism, MYC and HIF-1A, while concomitantly derepressing a pro-apoptotic stress sensor. Together, these studies reveal a promising therapeutic strategy for CRPC and demonstrate how metabolic plasticity can be fatally impaired by co-targeting upstream oncogenic nodes that converge on this important process.

Keywords:  Cancer; Cell biology; Metabolism; Oncology; Signal transduction; Therapeutics

DOI:  https://doi.org/10.1172/JCI203835
Biochem Biophys Res Commun. 2026 Jun 05. pii: S0006-291X(26)00874-0. [Epub ahead of print]828 154110

Cold atmospheric plasma selectively induces toxicity of prostate cancer cells associated with oxidative stress.

Imen Ghzaiel, Maxime Moreau, Souwaidi Ali, Rohan Quoniou, Silvère Baron, Frédéric Perisse, Jean-Marc Lobaccaro, Sébastien Menecier.

  Cold atmospheric plasma (CAP) is an ionized gas generated at atmospheric pressure in which the temperature of heavy particles (ions, molecules, atoms) remains close to room temperature. CAP produces a complex mixture of reactive oxygen and nitrogen species (RONS). Recent studies have demonstrated its ability to induce cell death in various cancer cell lines, both in vitro and in vivo. Interestingly, non-tumoral cells appear to be relatively less affected by CAP treatments, this phenomenon is referred to as CAP selectivity. This study aimed to investigate the differential selectivity of a CAP jet generated by dielectric barrier discharge (DBD) in human prostate cells, comparing prostate cancer PC3 cells with non-tumoral RWPE-1 cells. Cells were exposed to a CAP treatment for 5-60 s and cell viability (MTS assay), plasma membrane integrity (Propidium iodide, PI staining), morphology (phase-contrast microscopy), intracellular ROS production (DHE staining), and antioxidant enzyme activities (SOD (superoxide dismutase), catalase, GPx (glutathione peroxidase)) were assessed 4 h and 24 h post-treatment. CAP exposure induced a time-dependent decrease in PC3 cell viability, with significant effect on viability observed at exposures ≥30 s, whereas RWPE-1 cells showed relative resistance. PI staining confirmed greater plasma membrane damage in PC3 compared to RWPE-1 cells. Morphological alterations such as cell rounding and detachment were more pronounced in PC3 cells than RWPE-1. CAP markedly increased intracellular ROS levels in PC3 cells (up to 73% DHE-positive after 60 s), accompanied by SOD upregulation and reduced catalase and GPx activities. In contrast, RWPE-1 cells exhibited a less pronounced oxidative response and preserved antioxidant enzyme activities. In summary, these results demonstrate differential sensitivity to CAP treatment between prostate cancer cells and non-tumoral cells under the tested conditions, associated with alterations in cellular redox status. These findings suggest that DBD-generated CAP may represent a promising targeted therapeutic approach for prostate cancer treatment.

Keywords:  Antioxidant enzymes; Cell viability; Cold atmospheric plasma; Dielectric barrier discharge; Oxidative stress; Prostate cancer; Reactive oxygen and nitrogen species; Selective cytotoxicity

DOI:  https://doi.org/10.1016/j.bbrc.2026.154110
Neoplasia. 2026 Jun 09. pii: S1476-5586(26)00054-0. [Epub ahead of print]78 101324

Targeting the ELF1/EGFR/ERK positive feedback loop overcomes resistance to androgen receptor inhibition in AR-Vs positive prostate cancer.

Menghan Zhou, Longxin Deng, Xianglan Chen, Guanglin Yang, Yurun Huang, Chunlin Zhang, Yiping Yang, Yingxi Mo, Zhao Li, Shanshan Luo, Qingyun Zhang, Shan Wang.

  While anti-androgen therapies have significantly improved survival outcomes for patients with advanced prostate cancer, their efficacy is often limited by the emergence of resistance. This resistance is largely driven by the expression of AR splice variants (AR-Vs). However, therapeutic strategies to effectively target AR-V-mediated castration-resistant PCa remain an unmet clinical need. Here, we report that prolonged exposure of PCa cells expressing both AR-FL and AR-Vs to enzalutamide induces extensive reprogramming of their transcriptomic and proteomic profiles. Notably, in enzalutamide-resistant cells, EGFR expression was upregulated at both the mRNA and protein levels, despite the absence of EGFR mutations. Downstream of EGFR, the extracellular signal-regulated kinase (ERK) pathway was constitutively activated, promoting tumor cell proliferation. Furthermore, protein array analyses of clinical specimens revealed that high EGFR protein levels-but not EGFR mRNA levels-were associated with poor patient prognosis. In addition, we demonstrated that inhibiting EGFR, either through genetic knockdown or pharmacological intervention, significantly sensitized AR-V-mediated enzalutamide-resistant cells to AR-targeted therapy (Enzalutamide or Mithramycin). Mechanistically, our data indicate that ELF1 transcriptionally regulates EGFR and that ERK1/2 interacts with ELF1, suggesting the existence of a positive ELF1/EGFR/ERK feedback loop that sustains resistance. This study elucidates a possible mechanism of resistance to AR inhibition driven by an ELF1/EGFR/ERK feedback loop in AR-Vs positive cells and provides a rationale for combining EGFR inhibitors with AR-targeted therapy as a potential treatment strategy for patients with advanced, enzalutamide-resistant prostate cancer.

Keywords:  AR inhibition; AR-Vs; ELF1/EGFR/ERK; Enzalutamide resistance; Prostate cancer; Therapeutic vulnerability

DOI:  https://doi.org/10.1016/j.neo.2026.101324
J Appl Genet. 2026 Jun 13.

Prognostic alternative mRNA splicing signature and immune infiltration in prostate cancer.

Zewen Wang, Jian Tu, Rujiao Yin, Peicheng Shang, Chi Zhang, Yibin Zhou, Lijun Xu, Jin Zhu, Yachen Zang.

  Prostate cancer (PCa) is among the most prevalent malignancies in males across the globe. Alternative splicing (AS), a post-transcriptional modification, has been associated with several malignancies. This research focused on genome-wide analyses of AS events in PCa. Using gap analysis, we detected remarkable differential AS events (DASEs) related to PCa. Cox analysis was conducted to identify DASEs that prognostically affect the disease-free interval (DFI) and overall survival (OS) in PCa patients. Unsupervised cluster analysis was utilized to identify differential AS clusters and AS networks. We investigated whether patients with PCa who had a higher or lower risk of OS responded to chemotherapeutic and immunotherapeutic treatments. In the analysis of PCa, 296 DASEs were identified as clinically significant. The prognostic values for DFI and OS were used to construct a prognostic model. Using unsupervised cluster analysis, we determined the AS clusters related to OS. According to our findings, high- and low-risk groups have different outcomes for cisplatin and docetaxel chemotherapy. We conducted a detailed investigation of AS events in PCa by performing a genome-wide analysis. According to the data presented here, DASEs and splicing factors tend to influence the survival rates of PCa patients as well as their susceptibility to chemotherapeutic medications. This could offer innovative perspectives for the treatment of PCa.

Keywords:  Alternative splicing (AS); Prognosis signature; Prostate cancer (PCa); Regulatory network; Splicing factor (SF)

DOI:  https://doi.org/10.1007/s13353-026-01085-4
bioRxiv. 2026 May 29. pii: 2026.05.26.727474. [Epub ahead of print]

A Novel Drug Candidate that Selectively Targets the Critical Androgen Receptor-ELK1 Growth Axis in Advanced and Drug-Resistant Prostate Cancer.

Claire Soave, Lisa Polin, Charles Ducker, Vy Ong, Seongho Kim, Luke Pardy, Jing Li, Xun Bao, Yanfang Huang, Peter E Shaw, Rahul Khupse, Manohar Ratnam.

Androgen receptor (AR)-dependent prostate cancer (PCa) cells require co-activation of ELK1 by AR to activate a critical set of cell cycle and mitosis genes, regardless of hormone - sensitivity. A small molecule antagonist (KCI807) that inhibits AR-dependent growth by selectively binding to AR and blocking its association with ELK1 is limited as a drug by auto-induced metabolism. Using structure-activity data, consistent with modeling a physically mapped KCI807 binding pocket, we developed a new class of compounds with a different core structure comprising 5-Hydroxy-2-(3-hydroxyphenyl)-1-methylquinolin-4(1H)-one (KCI830), with variable N- substituents. The compound with a N-2,2,2-trifluoroethyl substitution (KCI838) was the fastest acting and most potent inhibitor of AR-dependent cell growth and colony formation in PCa model cells, including exclusively AR splice variant-dependent and other enzalutamide-resistant cells, without affecting growth of AR-negative cell lines. Critical tests were conducted to establish that KCI838 recapitulates the previously elucidated mode of action of KCI807. KCI838 selectively inhibited ELK1-dependent vs. androgen response element (ARE)-driven promoter and gene activation by AR. KCI838 blocked AR binding to ELK1 in situ tested by BRET assay. Increasing the total cellular AR by ∼2-fold using ectopic AR expression caused the predicted change in drug dose-response profile for growth, implicating AR as the exclusive target for the activity of KCI838. KCI838's molecular scaffold conferred reduced enzyme induction in primary human hepatocytes and weakened interactions with human UGT1A1 and CYP1A2. In mice bearing an aggressive, enzalutamide-resistant patient-derived PCa tumor xenograft characteristically overexpressing prostatic acid phosphatase, daily bolus injections of a soluble 3'phosphate monoester prodrug of KCI838 (KCI838PME) progressively inhibited tumor growth, concomitant with tumor accumulation of active hydrophobic drug, without significant toxicity. Additionally, ALZET osmotic pumps were used to establish proof-of-concept for reversible in vivo anti-tumor activity of KCI838PME administered in a low dose, controlled release mode. The results warrant investigation of KCI838PME in a controlled-release formulation, to treat PCa that is resistant to current AR-targeted therapies while obviating the need for testosterone suppression.

DOI: https://doi.org/10.64898/2026.05.26.727474
MedComm (2020). 2026 Jun;7(6): e70760

Single-Cell and Spatial Transcriptomics Uncover Immune Dynamics and Cellular Heterogeneity in Benign Prostatic Hyperplasia and Prostate Cancer Transition.

Yuanyuan Luo, Haitao Zhong, Tongrui Shang, Bin Hu, Dongbo Yuan, Xueyuan Jia, Ruichong Lin, Zehua Wang, Yinyi Fang, Guohua Zhu, Jukun Song, Zhangcheng Liu, Bo Yan, Fa Sun, Zhenyu Jia, Yunfang Yu, Luhui Mao, Hai Huang, Jianguo Zhu.

  Prostate cancer (PCa) is frequently accompanied by benign prostatic hyperplasia (BPH), highlighting the need to reassess their correlation in tumor risk, malignant progression, and immune status to improve the early diagnosis and treatment of PCa. In this study, single-cell RNA sequencing and spatial transcriptomics were used to analyze the potential association between normal, BPH, and PCa tissues. Our study revealed a continuous transformation map of luminal epithelial cells from hyperplasia to malignancy in BPH and PCa, accompanied by a persistently suppressive immune microenvironment. In the lesion nodules, T cells showed a high degree of infiltration yet showed activation retardation and functional exhaustion. Macrophages were also significantly infiltrated, exhibiting significant M2 polarization characteristics, and inflammatory signaling pathways related to immune escape were activated. Natural killer (NK) cells and B cells were partially activated, yet the low abundance of NK cells and B cells resulted in functional limitations. Our results revealed the dynamic changes of the immune landscape during the occurrence and progression of PCa. Our classification and prognostic models provide a theoretical basis for immunomodulatory and personalized therapies and provide new tools for the early diagnosis and intervention of PCa.

Keywords:  benign prostatic hyperplasia; continuous transformation map; immune microenvironment; prostate cancer; single‐cell RNA sequencing; spatial transcriptomics

DOI:  https://doi.org/10.1002/mco2.70760
Oncogene. 2026 Jun 06.

MCCC2 stabilizes LTBP1 via suppressing SMURF1-dependent ubiquitination to drive bone metastasis in prostate cancer.

Minsheng Yang, Yutong Chen, Shufen Lai, Xinyue Liang, Jianxin Cai, Kangqiang Weng, Wenping Lin, Weiyu Zhang.

Prostate cancer (PCa) is one of the most common malignancies in men globally, with bone metastasis being a leading cause of death in advanced disease. Emerging evidence links methylcrotonyl-CoA carboxylase subunit 2 (MCCC2) to the migratory and invasive capacities of PCa cells, but its regulatory mechanisms in bone metastasis and therapeutic potential remain unclear. Here, liquid chromatography-mass spectrometry identified LTBP1 as a direct interacting partner of MCCC2, validated by co-immunoprecipitation and GST pulldown assays. Functional studies demonstrated that MCCC2 promotes PCa cell migration, invasion in vitro, and bone metastasis in vivo. Mechanistically, MCCC2 competitively inhibits SMURF1-mediated ubiquitination and degradation of LTBP1, stabilizing LTBP1 to activate TGF-β signaling. Clinically, high MCCC2 expression correlates with elevated LTBP1 levels, increased bone metastasis incidence, and poor prognosis in PCa patients. These findings reveal that MCCC2 drives PCa bone metastasis via the LTBP1-TGF-β axis, highlighting MCCC2 as a promising therapeutic target for preventing or treating bone metastasis.

DOI: https://doi.org/10.1038/s41388-026-03843-4
Int J Mol Sci. 2026 Jun 02. pii: 5017. [Epub ahead of print]27(11):

Integrated Single-Cell RNA-Seq and Machine Learning to Construct an EMT Infiltration Scoring Model for Prostate Cancer.

Zhipeng Xie, Yingjie Sun, Yuheng Tang, Qi Qi, Jiaxiang Liang, Jiehui Zhang, Wenru Tang, Xuhong Zhou.

  Prostate cancer (PCa) remains a major global health concern, with a subset of patients progressing to aggressive disease despite advances in diagnosis and treatment. Epithelial-mesenchymal transition (EMT) plays a pivotal role in tumor invasion, metastasis, and immune evasion; however, its cellular heterogeneity and clinical relevance in PCa remain incompletely understood. We analyzed single-cell transcriptomic data to characterize EMT dynamics in malignant epithelial cells. Malignant cells were identified based on aberrant copy number variation patterns, and EMT activity was quantified using AUCell. Gene expression profiling and gene set enrichment analysis identified key EMT-associated genes. By integrating bulk transcriptomic data with LASSO regression analysis, we identified five pivotal genes and constructed an EMT infiltration scoring model. The model demonstrated robust predictive performance in an external Gene Expression Omnibus validation cohort and effectively predicted early biochemical recurrence. Further analyses revealed significant associations between EMT scores, clinicopathological features, immune cell infiltration, genomic instability, and tumor immune dysfunction and exclusion scores. Pathway enrichment analysis highlighted distinct molecular characteristics between high- and low-score groups. Additionally, molecular docking using AutoDock identified potential targeted therapeutic agents for key EMT genes. Overall, this study systematically delineates EMT heterogeneity at the single-cell level and establishes a robust EMT infiltration model for prognostic prediction and therapeutic guidance in PCa, providing novel insights for precision risk stratification and individualized treatment strategies.

Keywords:  biochemical recurrence; copy number variation (CNV); epithelial–mesenchymal transition; immune checkpoint; machine learning; prostate cancer; single-cell analysis; tumor immune microenvironment

DOI:  https://doi.org/10.3390/ijms27115017
Prostate Cancer. 2026 ;2026 9093252

Metformin and Flutamide Combination Therapy's Efficacy and Safety in Prostate Cancer Cell Lines.

AhmadReza Rezaeian, Fatemeh Khatami, Seyed Reza Hosseini, Iman Menbari Oskouie, Akram Mirzaei, Rahil Mashhadi, Helia Azodian Ghajar, Mahdi Khoshchehreh, Ali Tavoosian, Seyed Mohammad Kazem Aghamir.

   Background: Considering the hepatotoxicity and other side effects associated with flutamide as a first-line treatment for prostate cancer (PCa), this study aimed to evaluate metformin as a potential anticancer agent to reduce the required dose of flutamide and thereby minimize its adverse effects.
Method: We assessed the influence of metformin, flutamide, and metformin-flutamide combination therapy on LNCaP, DU145, and PC3 cell lines, which represent human PCa. The tests include wound-healing assay, colony formation assay (CFA), analysis of apoptosis (programmed cell death) and cell cycle by flow cytometry, gene expression at the mRNA level by real-time PCR (BAX/BCL2, E-cadherin, Snail, HIF1α, VEGFC, and KLK3 genes), and assessment of the treatments' hepatotoxicity potential via measuring AST and ALT values.
Result: To determine the IC50 (half-maximal inhibitory concentration) values, cell lines were treated with different concentrations of the drugs. The IC50 values for metformin (800 μM) in the three cell lines and for flutamide (12 μM for PC3 and 10 μM for LNCaP/DU145), as determined by MTT assay, were confirmed by flow cytometry, indicating significant cell cycle arrest at the G0/G1 phase. The combination of metformin and flutamide significantly increased the BAX/BCL2 mRNA ratio in all three cell lines (p < 0.0001) and downregulated the expression of KLK3 (p < 0.01), HIF1α (p < 0.01), VEGFC (p < 0.001), and EMT pathway genes in PC3 and LNCaP (p < 0.01). Liver injury assessment reported a reduction in flutamide's hepatotoxicity in combination with metformin.
Conclusion: Metformin in combination with flutamide reduced its dose and increased the sensitivity of PCa cells to treatment. Additionally, it mitigated the hepatotoxic effects of flutamide. Therefore, this combination may represent a new treatment strategy for PCa.

Keywords:  combination therapy; flutamide; metformin; prostate cancer

DOI:  https://doi.org/10.1155/proc/9093252