bims-meproc 2025-10-05 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–10–05
24 papers selected by
Grigor Varuzhanyan, UCLA

Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer.
Natural Products Targeting the Androgen Receptor Signaling Pathway: Therapeutic Potential and Mechanisms.
Targeting FOXA1 and FOXA2 disrupts the lineage-specific oncogenic output program in prostate cancer.
LIAS Promotes Cuproptosis in Prostate Cancer Cells by Suppressing Glycolysis via the p53 Signaling Pathway.
Novel Afro-Caribbean Prostate Cancer Model Reveals Ancestry-Specific Drug Vulnerabilities with Therapeutic Implications for Black Patients.
Single-cell analysis uncovers preserved prostate cancer lineages and universally altered pathways in Matrigel-free patient-derived organoids.
ZKSCAN5 transcriptional regulation of APOC1 modulates ferroptosis via PI3K/AKT/SREBP2/SLC1A5 axis.
Extracellular vesicles-mediated delivery of CRISPR machinery silences androgen receptor in castration-resistant prostate cancer cells.
SOX4-Mediated Post-Transcriptional suppression of PTEN via miR-106b~25 Cluster Contributes to Prostate Cancer Aggressiveness.
CBP/p300, a promising therapeutic target for prostate cancer.
Targeting polyamine metabolism induces oxidative/carbonyl stress to reinvigorate antitumor immunity in prostate cancer.
Spatial metabolomics strategy reveals heterogeneity of prostate cancer based on multi-platform imaging and laser microdissection-gas chromatography-tandem mass spectrometry.
IGFBP2 alteration contributes to prostate cancer progression by modulating prostate stroma activation.
Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer.
Biomarkers in Prostate Cancer: What's in the Blood?
Constitutive NF-κB Activation is Amplified by VSV in Aggressive PC3 Prostate Cancer Cells that Resist Viral Oncolysis.
Integrated Lipidomics and Chinmedomics Reveal the Multi-Target Mechanism of Phellodendri Amurensis Cortex in Prostate Cancer via Lipid Metabolism Remodeling.
Preclinical activity of the DLL3-targeted T cell engager MK-6070 in neuroendocrine prostate cancer.
The future of androgen receptor targeting in prostate cancer: third-generation inhibitors and beyond.
miR-145-5p and miR-148b-3p Expression Is Inversely Associated with Pten Expression in Prostate Pathologies.
Comprehensive analysis of androgen receptor splice variant target gene expression in prostate cancer.
Evaluating the prognosis of prostate cancer through metabolic pathways.
Identification of progression markers for prostate cancer.
Treatment options in hormone-sensitive prostate cancer: targeting the androgen-sensitive pathway.

bioRxiv. 2025 Apr 30. pii: 2023.11.15.567250. [Epub ahead of print]

Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer.

Fahim Ahmad, Margaret White, Kazutoshi Yamamoto, Daniel R Crooks, Supreet Agarwal, Ye Yang, Brian Capaldo, Sonam Raj, Aian Neil Alilin, Anita Ton, Stephen Adler, Jurgen Seidel, Colleen Olkowski, Murali Krishna Cherukuri, Peter L Choyke, Kathleen Kelly, Jeffrey R Brender.

Advanced prostate cancer is treated with androgen receptor (AR) signaling inhibitors, which are initially effective, but most patients eventually develop resistance and progress to castrate-resistant prostate cancer (CRPC). Loss of RB1 in CRPC tumors is correlated with rapid progression and poor patient survival and, in combination with TP53 loss, predisposes patients to the development of transitional neuroendocrine prostate cancer (NEPC). Although progressive CRPC is clinically associated with higher 18FDG-PET SUVmax values, it is unknown whether inactivation of RB1 and/or TP53 is a driver of increased glucose import. Using a cohort of patient-derived xenograft (PDX)-derived CRPC organoids, we found that NEPC could not be conclusively distinguished from adenocarcinoma by 18FDG uptake alone, and PSMA protein levels did not correlate with cancer phenotype or 18FDG uptake. Castration-resistant models showed higher 18FDG uptake, but lower pyruvate-to-lactate conversion compared to their castration-sensitive counterparts. In parallel studies using castration-sensitive prostate cancer models, RB1/TP53 knockdown did not affect 18FDG uptake, but increased basal respiration and glycolytic activity, with combined depletion leading to glucose diversion into glycogenesis. These metabolic changes were reflected in increased lactate dehydrogenase flux detected by 13C-hyperpolarized magnetic resonance spectroscopy upon RB1 loss, but not in 18FDG uptake. The metabolic heterogeneity revealed here suggests that a multimodal molecular imaging approach can improve tumor characterization, potentially leading to a better prognosis in cancer treatment.

DOI: https://doi.org/10.1101/2023.11.15.567250
Curr Issues Mol Biol. 2025 Sep 19. pii: 780. [Epub ahead of print]47(9):

Natural Products Targeting the Androgen Receptor Signaling Pathway: Therapeutic Potential and Mechanisms.

Sitong Wu, Esveidy Isabel Oceguera Nava, Dennis Ashong, Guanglin Chen, Qiao-Hong Chen.

  The androgen receptor (AR) signaling pathway is the primary driver of prostate cancer initiation and progression, including the development of castration-resistant prostate cancer (CRPC). Because current AR-targeted therapies inevitably encounter drug resistance, novel strategies to suppress AR signaling are urgently needed. Natural products represent a rich and structurally diverse source of bioactive compounds capable of targeting AR at multiple regulatory levels. This review overviews the interactions between natural products and the AR signaling axis through distinct mechanisms, including inhibition of testosterone production and 5α-reductase activity, direct antagonism of AR, and induction of AR degradation. In addition, several compounds disrupt AR nuclear translocation, downregulate AR splice variants, or suppress AR signaling indirectly through epigenetic regulation, microRNA modulation, or interference with co-regulator networks. Preclinical studies provide compelling evidence that these agents can effectively interrupt AR signaling, thereby suppressing prostate cancer growth. However, challenges remain, particularly the limited pharmacokinetic characterization, lack of in vivo validation, and scarcity of clinical studies. Future research should focus on improving bioavailability, exploring synergistic combinations with existing therapies, and advancing well-designed in vivo and clinical investigations. Collectively, these efforts may establish natural products as lead compounds to modulate AR signaling for prostate cancer prevention and treatment.

Keywords:  androgen receptor; antagonism; degradation; natural product; testosterone

DOI:  https://doi.org/10.3390/cimb47090780
Cell Rep. 2025 Sep 26. pii: S2211-1247(25)01095-2. [Epub ahead of print]44(10): 116324

Targeting FOXA1 and FOXA2 disrupts the lineage-specific oncogenic output program in prostate cancer.

Nicolo Formaggio, Jacopo Sgrignani, Gayathri Thillaiyampalam, Claudio Lorenzi, Giada A Cassanmagnago, Marco Coazzoli, Federico Costanzo, Yanick Uebelhart, Daniela Bossi, Diego Camuzi Cassiano, Andrea Rinaldi, Matteo Pecoraro, Roger Geiger, Raffaella Santoro, Marco Bolis, Andrea Cavalli, Jean-Philippe Theurillat.

  Activation of the androgen receptor (AR) is the key lineage-specific oncogenic pathway and the primary therapeutic target in prostate cancer. While AR signaling is enabled by the pioneer transcription factor FOXA1, its homolog FOXA2 is specifically expressed in advanced lineage-plastic prostate cancers that have lost the AR signaling axis. However, their roles and utility as drug targets remain incompletely characterized. Here, we show an unexpected collaboration of FOXA1 and FOXA2 in mediating AR-independent cell proliferation in different lineage-plastic cancer subtypes. Conversely, joint loss-of-function or pharmacologic disruption of FOXA1 and FOXA2 leads to the collapse of lineage-specific oncogenic transcription factors followed by cell-cycle arrest. In summary, our findings uncover a druggable dependency for AR-positive and -negative prostate cancers.

Keywords:  CP: Cancer; FOXA1; FOXA2; androgen receptor independence; androgen receptor signaling; lineage plasticity; pioneer transcription factor; prostate cancer; small molecule inhibitor

DOI:  https://doi.org/10.1016/j.celrep.2025.116324
Prostate. 2025 Oct 01.

LIAS Promotes Cuproptosis in Prostate Cancer Cells by Suppressing Glycolysis via the p53 Signaling Pathway.

Zhe Tang, Peichao Guo, Yuanhua Liu.

   BACKGROUND: Cuproptosis holds significant potential for optimizing cancer therapeutic strategies. However, the molecular mechanism by which lipoic acid synthase (LIAS) regulates cuproptosis in prostate cancer (PC) remains unclear.
METHODS: The GEPIA online tool and PC cell lines were used to analyze the expression of LIAS in PC. Cuproptosis characteristics were assessed using Cu²⁺ detection kits, Western blot (LIAS/FDX1), and immunofluorescence (DLAT oligomerization). Cell viability and proliferation capacity were determined by CCK-8 and colony formation assays. qPCR was used to detect p53 pathway gene expression. Glycolytic activity was analyzed by measuring extracellular acidification rate (ECAR), glucose uptake, and ATP levels. The regulatory relationship was validated using glycolytic inhibitors within the cuproptosis model.
RESULTS: LIAS expression was significantly downregulated in both PC and cuproptosis models. Overexpression of LIAS enhanced cuproptosis effects and suppressed the viability and proliferative capacity of cancer cells. Further analysis revealed that LIAS suppressed glycolysis by activating the p53 pathway, manifested by decreased extracellular acidification rate (ECAR), reduced glucose uptake, and diminished ATP levels. Notably, inhibition of glycolysis promoted cuproptosis, thereby impeding tumor progression.
CONCLUSION: LIAS promotes cuproptosis and inhibits cancer cell proliferation in PC by activating the p53 signaling pathway to suppress glycolytic activity. These findings indicate that LIAS represents a potential therapeutic target for intervening in PC, and regulation of the glycolysis-cuproptosis axis may serve as an effective strategy for improving PC progression.

Keywords:  LIAS; cuproptosis; glycolysis; p53; prostate cancer

DOI:  https://doi.org/10.1002/pros.70049
Cancer Res Commun. 2025 10 01. 5(10): 1758-1770

Novel Afro-Caribbean Prostate Cancer Model Reveals Ancestry-Specific Drug Vulnerabilities with Therapeutic Implications for Black Patients.

Simone Badal, Bor-Jang Hwang, Ashlianne Nelson, Kristoff Frank, Tanisha Maitre, Magdalene Nwokocha, Rory Thompson, Belinda Morison, Rajini Haraksingh, Valerie Odero-Marah, Camille Ragin.

In the era of targeted therapeutics, the inadequate representation of Black populations in prostate cancer models limits effective drug screening. In this study, we introduce ACRJ-PC28, a novel Afro-Caribbean prostate cancer cell line, and evaluate its responses to five anticancer drugs (docetaxel, cabazitaxel, abiraterone, olaparib, and enzalutamide) and betaine. We compare these responses with those of established prostate cancer cell lines from Black (MDA-PCA-2b) and White (DU-145 and PC-3) donors using three distinct viability assays. We observed ancestry-dependent drug sensitivities: abiraterone showed remarkable selectivity for ACRJ-PC28 (IC50 = 1.10 μmol/L), being 4.6- to 13.1-fold more potent than in other cell lines, whereas enzalutamide demonstrated pronounced racial differences, being 3 to 5 times less effective in cell lines from Black donors (IC50 = 206 μmol/L for ACRJ-PC28; 104 μmol/L for MDA-PCA-2b) versus cell lines from White donors (IC50 = 37 μmol/L for PC-3; 48 μmol/L for DU-145). RNA sequencing analysis revealed consistent underexpression of TNF family genes, particularly TNFRSF14, in prostate cancer cells from Black donors correlating with differential drug responses. Despite underexpressing AR, the ACRJ-PC28 line exhibited exceptional sensitivity to abiraterone, consistent with clinical observations that Black patients with prostate cancer respond better to this therapy. This aligns with its neuroendocrine phenotype in the source patient, who succumbed within 1 year despite androgen deprivation therapy. Our findings suggest that incorporating diverse prostate cancer models in preclinical screening could guide personalized treatment strategies for Black patients who experience disproportionate prostate cancer mortality by identifying ancestry-specific drug vulnerabilities that inform optimal therapeutic combinations.
SIGNIFICANCE: This study introduces ACRJ-PC28, the first Afro-Caribbean prostate cancer cell line, revealing ancestry-dependent drug sensitivities that could explain differential clinical outcomes. The findings demonstrate critical gaps in current preclinical models and support incorporating diverse cell lines to develop personalized treatment strategies for underrepresented populations experiencing disproportionate cancer mortality.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0254
Cell Rep. 2025 Sep 30. pii: S2211-1247(25)01123-4. [Epub ahead of print]44(10): 116352

Single-cell analysis uncovers preserved prostate cancer lineages and universally altered pathways in Matrigel-free patient-derived organoids.

Robin Dolgos, Romuald Parmentier, Jing Wang, Raphaëlle Servant, Arnoud J Templeton, Tobias Zellweger, Alastair D Lamb, Kirsten D Mertz, Svetozar Subotic, Tatjana Vlajnic, Helge Seifert, Ashkan Mortezavi, Cyrill A Rentsch, Lukas Bubendorf, Clémentine Le Magnen.

  The application of patient-derived organoids (PDOs) in prostate cancer (PCa) research has been hampered by poor take rates and benign overgrowth. We highlight the limitations of existing culture conditions and identify extracellular matrix composition as a determinant of organoid outcome. Single-cell RNA sequencing reveals that Matrigel-free PDOs exhibit cellular heterogeneity, preserve patient-specific PCa cells with active androgen receptor signaling, and enrich in intermediate cells. In contrast, Matrigel fails to maintain primary PCa cells and produces in vitro basal-like features divergent from patient samples. Furthermore, we redefine cell-type signatures, identify biomarkers discriminating tumor versus other cell types, and show that expression of laminin-binding integrins is a hallmark of Matrigel-derived organoids. Finally, integrating previously published datasets with our data, we generate a prostate PDO single-cell atlas (PPScA), which captures a spectrum of cellular identities while revealing pathways altered in vitro. Our study provides methodological improvements for short-term culture and cellular biology insights.

Keywords:  CP: Cancer; CP: Stem cell research; PDOs; cancer models; cellular heterogeneity; culture conditions; ex vivo; extracellular matrix; patient-derived organoids; prostate cancer; single-cell RNA sequencing; single-cell atlas

DOI:  https://doi.org/10.1016/j.celrep.2025.116352
J Transl Med. 2025 Sep 30. 23(1): 1020

ZKSCAN5 transcriptional regulation of APOC1 modulates ferroptosis via PI3K/AKT/SREBP2/SLC1A5 axis.

Yongbo Liu, Zihao Qi, Shuo Yang, Yanze Li, Jia Guo.

   BACKGROUND: Prostate cancer is a great substantial health challenge among the cancer type with a high incidence and serving as the main cause of cancer-related deaths in men. Apolipoprotein C1 encodes a member of the apolipoprotein C family. The APOC1 has been confirmed as an oncogene of prostate cancer. However, the mechanism of how the APOC1 protein influence remains to be elucidated.
METHODS: The expression of APOC1 was detected in both prostate cancer tissues and prostate cancer cell lines. The APOC1 knockdown and overexpression cell models were created. The effect of APOC1 on prostate cancer cell proliferation,metastasis, EMT and ferroptosis were explored by colony formation, wound healing,transwell assays, CCK-8 and western blotting in vitro and subcutaneous tumor formation in nude mice. Furthermore, the mechanism of how APOC1 inhibits ferroptosis in prostate cancer through PI3K/AKT/SREBP2/SLC1A5 was detected. Meanwhile, the interaction of APOC1 and ZKSCAN5 (zinc finger with KRAB and SCAN domains 5) was determined using Chromatin Immunoprecipitation (ChIP).
RESULTS: APOC1 expression was significantly upregulated in prostate cancer tissues and cell lines. Genetic silencing of APOC1 by shRNA demostrated potent tumor-suppressive effects, markedly inhibiting cell proliferation, metastasis and EMT, while concurrently enhancing ferroptosis rates. Then, APOC1 was shown to modulate cholesterol homeostasis via the PI3K/AKT/SREBP2/SLC1A5 signaling cascade, thereby influencing ferroptosis susceptibility in prostate cancer cells. Mechanistically, ZKSCAN5 was identified as a transcriptional repressor of APOC1 through direct promoter binding. Notably, the anti-ferroptosis function of APOC1 was mediated through SREBP2-dependent transcriptional regulation, with Cut&Tag (Cleavage Under Targets and Tagmentation) confirming SREBP-2's direct binding to the SLC1A5 promoter.
CONCLUSION: In prostate cancer, APOC1 regulates ferroptosis via PI3K/AKT/SREBP2/SLC1A5 axis, meanwhile ZKSCAN5 negatively regulates the expression of APOC1.

Keywords:  APOC1; EMT; Ferroptosis; Metastasis; PI3K/AKT/SREBP2/SLC1A5 axis; Proliferation; Prostate cancer; Transcription factor; ZKSCAN5

DOI:  https://doi.org/10.1186/s12967-025-07092-z
Mol Ther. 2025 Sep 27. pii: S1525-0016(25)00816-0. [Epub ahead of print]

Extracellular vesicles-mediated delivery of CRISPR machinery silences androgen receptor in castration-resistant prostate cancer cells.

Chenming Ye, Yongjie Ma, Raunak Shrestha, Jingwen Cai, Yutao Liu, Liu Peng, Jindan Yu, Houjian Cai.

CRISPR-mediated gene editing is a promising technology for treatment of diseases by silencing a driver gene at the genomic DNA level. However, delivery of CRISPR machinery remains challenging for potential therapeutic application. Here, we developed a platform using extracellular vesicles (EVs) as a vehicle to deliver Cas9/single guide RNA (sgRNA) ribonucleoprotein (RNP) complex to silence androgen receptor (AR) gene in prostate cancer (PCa) cells. A genetic modification conferred the N-myristoylation to the Cas9 protein, which enhanced the encapsulation of Cas9/sgRNA RNP into EVs and silenced both ectopic and endogenous AR gene. Interestingly, gene editing efficiency varied across PCa cell lines, associated with different chromatin accessibility at the target site. Functional analyses demonstrated that Cas9/sgRNA RNP (targeting the N-terminal domain of the AR gene) did not change gene-edited AR mRNA levels, but significantly inhibited expression levels of AR downstream genes, thereby attenuating PCa cell proliferation. Importantly, EVs-mediated delivery of the Cas9/sgRNA RNP introduced indels into the AR gene and inhibited proliferation of enzalutamide-resistant PCa cells. This study highlights a therapeutic strategy for treatment of castration-resistant PCa using a programmable EVs-mediated delivery platform.

DOI: https://doi.org/10.1016/j.ymthe.2025.09.045
Mol Cancer Res. 2025 Oct 01.

SOX4-Mediated Post-Transcriptional suppression of PTEN via miR-106b~25 Cluster Contributes to Prostate Cancer Aggressiveness.

Feifei Sun, Lin Gao, Meng Wang, Ping Liu, Baozhen Wang, Jing Hu, Weiqing Wang, Hui Liu, Bo Han.

Molecular based risk stratification of prostate cancer (PCa) holds significant potential for guiding precision therapeutic strategies. Previous studies revealed SOX4 activation drives PCa progression in PTEN deficient tumors through the PI3K-AKT signaling pathway. However, the mechanistic interplay between SOX4 and PTEN, as well as their clinical utility for prognostic stratification, remains to be elucidated. In this study, we revealed that SOX4 expression is increased in PCa patients with low PTEN levels, and the expression of SOX4 and PTEN is inversely correlated in PCa patients. Importantly, PCa patients exhibiting SOX4-high/PTEN-low (SOX4+/PTEN-) expression represent an aggressive PCa subtype associated with unfavorable prognosis. Mechanistically, we found that SOX4 downregulates PTEN protein expression at the post-transcriptional level. Through high-throughput microRNA profiling and bioinformatics analysis, we identified that SOX4 transcriptionally activates the expression of miR-106b∼25 cluster, which directly targets PTEN. Furthermore, SOX4 overexpression combined with PTEN deficiency leads hyperactivation of the PI3K-AKT pathway. Importantly, dual targeting of SOX4 and PI3K-AKT signaling effectively suppresses PCa cell proliferation, migration and invasion in vivo and in vitro. These data establish a novel SOX4/miR-106b~25/PTEN pathway model in promoting PCa progression and propose a potential therapeutic strategy for this high-risk subtype. Implications: SOX4 suppresses PTEN through the transcriptional upregulation of miR-106b~25, rendering tumors sensitive to combined inhibition of SOX4 and PI3K-AKT in prostate cancer.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0471
J Transl Med. 2025 Oct 02. 23(1): 1045

CBP/p300, a promising therapeutic target for prostate cancer.

Hongtao Xu, Yifan Hou, Zhenhua Zhao, Jianhua Zhang, Pan Li, Yujia Cao, Xiaobo Nie, Junqing Hou.

  Prostate cancer (PCa) remains the most prevalent malignancy among men, with the inevitable emergence of castration-resistant prostate cancer (CRPC) presenting the greatest challenge. Accumulating evidence has confirmed that the overexpression of cAMP response element-binding protein (CREB)-binding protein (CBP) and E1A-binding protein (p300), two highly homologous transcriptional coactivators, plays a crucial role in the development of PCa and its progression to CRPC, thereby making them prominent therapeutic targets for all types of PCa. In this review, we systematically discuss the structure and function of CBP/p300 and elucidate the detailed mechanisms by which CBP/p300 promote prostate carcinogenesis and development. Specifically, CBP/p300 facilitate prostate carcinogenesis by acetylating specific lysine residues on essential transcription factors involved in androgen receptor (AR) signaling, canonical Wnt signaling, p53 signaling, as well as other pathways such as PI3K/AKT and MAPK signaling. Additionally, they contribute to tumor immunosuppression and adaptive resistance to programmed death ligand 1 (PD-L1) blockade treatment by inducing the expression and secretion of the PD-L1 protein. Furthermore, we explore the latest advances in the use of various inhibitors targeting different domains of CBP/p300 and proteolysis-targeting chimeras (PROTAC) degraders in PCa. We propose that combing CBP/p300 inhibitors or degraders with current anti-PCa therapies, including androgen deprivation therapy (ADT), chemotherapy, and immunotherapy, holds potential to overcome the challenges in treating advanced PCa and improve clinical outcomes for all PCa patients.

Keywords:  AR signaling pathway; CBP/p300; Inhibitors; Prostate cancer; Therapeutic target; Wnt signaling pathways

DOI:  https://doi.org/10.1186/s12967-025-07053-6
J Control Release. 2025 Sep 30. pii: S0168-3659(25)00896-X. [Epub ahead of print] 114283

Targeting polyamine metabolism induces oxidative/carbonyl stress to reinvigorate antitumor immunity in prostate cancer.

Aijing Zhang, Jianguo Zheng, Yingying Xu, Shuai Fu, Qinglong Du, Chengyang Zhao, Yuxiang Meng, Mengqi Li, Lin Wang, Shuliang Wang, Tongrui Shi, Chen Yang, Peihong Jiang, Yiping Wang, Zhongwei Zhao, Zhao Zhang, Shuo Zhao, Xin Qin, Huimin Geng, Nengwang Yu.

  Immunotherapy of prostate cancer (PCa) remains challenging due to the immunosuppressive nature of the tumor microenvironment (TME). Oxidative damage enhances immunogenic cell death (ICD) to counteract immunotherapy resistance in PCa, but is limited by tumor antioxidant defenses and single-modality reactive oxygen species (ROS) generation in the TME. Herein, we report an innovative polyamine-based strategy that overproduces hydrogen peroxide and acrolein to simultaneously induce oxidative/carbonyl stress while suppressing endogenous antioxidant systems, thereby synergistically amplifying oxidative/carbonyl damage, which triggers robust ICD and achieves potent antitumor efficacy. Both in vitro and in vivo assays demonstrated that the nanoparticles, modified with a PCa-targeting peptide, could generate acrolein to induce mitochondrial destruction, DNA damage, and accumulate lipid peroxidation. In addition, they enhanced the recruitment of mature dendritic cells and T cells within the TME, thus inhibiting lung metastasis and tumor rechallenge. This work proposes an immunotherapy strategy using polyamine metabolism to induce combined carbonyl and oxidative stress, providing a novel approach for overcoming cold TME resistance in advanced PCa.

Keywords:  Immunogenic cell death; Nanoparticle; Polyamine; Prostate cancer; Reactive oxidative stress

DOI:  https://doi.org/10.1016/j.jconrel.2025.114283
Talanta. 2025 Sep 28. pii: S0039-9140(25)01412-2. [Epub ahead of print]298(Pt A): 128921

Spatial metabolomics strategy reveals heterogeneity of prostate cancer based on multi-platform imaging and laser microdissection-gas chromatography-tandem mass spectrometry.

Siming Pu, Peng Dou, Tianrun Xu, Chunmeng Wei, Yanli Li, Lina Zhou, Fubo Wang, Xin Lu, Xinyu Liu, Guowang Xu.

  Prostate cancer (PCa) exhibits significant intra-tumor metabolic heterogeneity. In this study, we developed a multi-platform workflow combining pathological staining, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), and laser capture microdissection-assistant gas chromatography-tandem mass spectrometry (LCM-GC-MS/MS) to investigate the metabolic spatial heterogeneity of a specific PCa tissue. Four suspicious glandular regions were initially identified by histology and immunofluorescence. MALDI-MSI revealed three distinct metabolic patterns for further analysis. It was found that only one glandular region showed PCa metabolic features, enabling precise differentiation from other regions of interest. The information from LCM-GC-MS/MS complemented that from MSI by confirming and quantifying fatty acid alterations. This workflow broadened the spatial metabolic coverage and enhanced intra-tumor metabolic heterogeneity analysis in PCa.

Keywords:  Laser capture microdissection; MALDI-MSI; Metabolic heterogeneity; Multi-platform imaging; Prostate cancer; Spatial metabolomics

DOI:  https://doi.org/10.1016/j.talanta.2025.128921
Cell Commun Signal. 2025 Oct 02. 23(1): 408

IGFBP2 alteration contributes to prostate cancer progression by modulating prostate stroma activation.

Mingguo Huang, Shintaro Narita, Hiromi Sato, Yuya Sekine, Mizuki Kobayashi, Soki Kashima, Ryohei Yamamoto, Atsushi Koizumi, Taketoshi Nara, Kazuyuki Numakura, Mitsuru Saito, Hiroshi Nanjo, Takayuki Ikezoe, Tomonori Habuchi.

   BACKGROUND: Insulin-like growth factor (IGF) binding protein-2 (IGFBP2) is a secretory protein that modulate the activity of IGFs. It is highly expressed in various cancers such as prostate cancer (PCa), in which it may play a controversial role in tumor progression, however, the molecular mechanisms of IGFBP2 in PCa progression remain unclear.
METHODS: In this study, we examined the expression pattern and role of IGFBP2 in PCa cells and the stroma during prostate tumor cell progression.
RESULTS: IGFBP2 was highly expressed in LNCaP cells and prostate stromal fibroblasts (PrSC) and was mainly secreted by PrSCs. Tumor cell growth and invasiveness were not directly affected by treatment with IGFBP2 siRNAs (siIGFBP2) or recombinant IGFBP2 (rIGFBP2). However, decreased expression of IGFBP2 significantly increased PrSC activation and the secretion of pro-tumorigenic cytokines IL-6, IL-8, IP10, and CCL5 through upregulation of TGF-β, which subsequently enhanced prostate tumor cell progression. Clinically, low expression of stromal IGFBP2 was associated with a high reactive prostate stroma, advanced PCa progression, and increased IGFBP2 levels in the serum.
CONCLUSION: Here, we provide mechanistic evidence that IGFBP2 act as a critical regulatory factor in the activation of prostate stromal microenvironment and contributes to aggressive PCa progression.

Keywords:  IGFBP2; Insulin-like growth factor binding protein-2; Prostate cancer; Prostate stromal cells

DOI:  https://doi.org/10.1186/s12964-025-02414-6
Nat Genet. 2025 Oct 03.

Targeting histone H2B acetylated enhanceosomes via p300/CBP degradation in prostate cancer.

Jie Luo, Zhixiang Chen, Yuanyuan Qiao, Jean Ching-Yi Tien, Eleanor Young, Rahul Mannan, Somnath Mahapatra, Rupam Bhattacharyya, Lanbo Xiao, Tongchen He, Sanjana Eyunni, Yuping Zhang, Yang Zheng, Fengyun Su, Xuhong Cao, Rui Wang, Yunhui Cheng, Rithvik Seri, James George, Miriam Shahine, Stephanie J Miner, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Ulka Vaishampayan, Mi Wang, Shaomeng Wang, Abhijit Parolia, Arul M Chinnaiyan.

Prostate cancer is driven by oncogenic transcription factor enhanceosomes comprising chromatin and epigenetic regulators. The lysine acetyltransferases p300 and CREB-binding protein (CBP) are key cofactors that activate enhancers through histone acetylation. Here we identify p300/CBP-mediated multisite histone H2B N-terminal acetylation (H2BNTac) as a defining feature of oncogenic enhanceosomes in androgen receptor (AR)-positive prostate cancer. p300/CBP are essential for AR and ETS transcription factor ERG transcriptional activity, and their dual degradation eliminates H2BNTac and histone H3 lysine 27 acetylation at hyperactive enhancers, leading to stronger suppression of oncogenic transcription than targeting either paralog or bromodomain alone. Cytotoxicity profiling across >900 cell lines revealed that tumors with high H2BNTac, including AR-positive prostate cancer, are selectively dependent on p300/CBP. In preclinical models, systemic p300/CBP degradation inhibited tumor growth, synergized with AR antagonists and showed no evident toxicity. These findings position H2BNTac as an epigenetic marker of enhancer addiction and establish dual p300/CBP degradation as a promising therapeutic strategy for enhancer-driven cancers.

DOI: https://doi.org/10.1038/s41588-025-02336-6
J Nucl Med. 2025 Oct 01. 66(10): 6A

Biomarkers in Prostate Cancer: What's in the Blood?
bioRxiv. 2025 Sep 25. pii: 2025.09.23.678061. [Epub ahead of print]

Constitutive NF-κB Activation is Amplified by VSV in Aggressive PC3 Prostate Cancer Cells that Resist Viral Oncolysis.

Alaa A Abdelmageed, Jack Smerczynski, Lute Douglas, Tori Russell, Matthew Morris, Stephen Dewhurst, Maureen C Ferran.

Cancer cells often have defects in antiviral pathways, making them susceptible to oncolytic viruses like vesicular stomatitis virus (VSV). However, some cancer cells resist viral infection through the constitutive expression of interferon-stimulated genes. This study examined whether NF-κB activation and NF-κB-dependent antiviral signaling contributes to resistance to VSV infection in the PC3 cell line, derived from an aggressive metastatic prostate cancer (PrCa) tumor. We found that NF-κB localized to the nucleus in VSV-infected PC3 cells, but not in the VSV-susceptible LNCaP PrCa cell line. Analysis of the upstream NF-κB inhibitor IκB- α revealed higher levels of both total and phosphorylated IκB- α in PC3 cells compared to LNCaP cells, indicating constitutive activation of the NF-κB pathway via an IκB-α-dependent mechanism. Notably, VSV infection did not alter IκB-α phosphorylation in PC3 cells, suggesting that VSV may amplify NF-κB signaling through an IκB- α -independent pathway. Furthermore, PC3 cells displayed elevated levels of the NF-κB p65 protein subunit compared to LNCaP cells, with its phosphorylated form significantly increased upon VSV infection. These results from phosphorylation assays confirm that multiple steps in the NF-κB pathway are differentially activated in PC3 and LNCaP cells. Additionally, the expression of several NF-κB-dependent cytokine and proinflammatory genes, including IL12 and IL6, were upregulated following VSV infection in PC3 cells, as compared to LNCaP cells. Blocking the NF-κB pathway using a pharmaceutical inhibitor resulted in increased PC3 cell death with VSV infection. Collectively, these findings suggest that enhanced NF-κB signaling may underlie the resistance of PC3 cells to VSV oncolysis, potentially offering new insights into therapeutic strategies targeting NF-κB in resistant prostate cancers.

DOI: https://doi.org/10.1101/2025.09.23.678061
J Ethnopharmacol. 2025 Oct 01. pii: S0378-8741(25)01366-2. [Epub ahead of print] 120674

Integrated Lipidomics and Chinmedomics Reveal the Multi-Target Mechanism of Phellodendri Amurensis Cortex in Prostate Cancer via Lipid Metabolism Remodeling.

Xianna Li, Luoning Bai, Le Yang, Zhigang Wang, Ying Han, Guanli Yan, Ye Sun, Hui Sun, Ling Kong, Qiuhan Li, Xijun Wang.

   ETHNOPHARMACOLOGICAL RELEVANCE: Phellodendri Amurensis Cortex (PAC), a traditional Chinese medicine exhibit diverse pharmacological activities, including anticancer effects. Lipid metabolic reprogramming in the tumor microenvironment (TME) drives prostate cancer (PCa) progression and represents a promising therapeutic target; however, the effects of PAC on TME lipid metabolism remain unclear.
AIM OF THE STUDY: To investigate the anti-PCa efficacy of PAC and its underlying mechanisms by evaluating targeting lipid metabolic dysregulation in the TME.
MATERIALS AND METHODS: A 22RV1 xenograft model was established in male BALB/c-nude mice. The therapeutic effects of PAC were evaluated using tumor growth inhibition, biochemical assays, histopathological analyses (Hematoxylin & Eosin and Oil Red O staining), TUNEL apoptosis analysis, and immunohistochemistry (Ki-67, CD31). Lipidomics was used to identify PAC-regulated lipid biomarkers and pathways. Chinmedomics and molecular docking were used to validated interactions between PAC bioactive components and core lipid-metabolizing enzymes.
RESULTS: PAC suppressed tumor growth, reduced intratumoral lipid accumulation, inhibited proliferation (Ki-67↓) and angiogenesis (CD31↓), and induced apoptosis (TUNEL↑). Thirty dysregulated lipid markers were identified in PCa, and PAC reversed 27 of them involved in glycerophospholipid, arachidonic acid, and sphingolipid metabolisms. Chinmedomics identified nine PAC components (e.g., berberine, magnoflorine) targeting phosphatidylserine synthase 1 (PTDSS1), phospholipase A and acyltransferase 3 (PLAAT3), phosphatidylethanolamine N-methyltransferase (PEMT), and phospholipase D family member 4 (PLD4), confirmed by molecular docking. These interactions disrupted phospholipid homeostasis and energy metabolism.
CONCLUSIONS: PAC exerts anti-PCa effects by reprogramming lipid metabolism via multi-component targeting of PTDSS1/PLAAT3/PEMT/PLD4, thereby inhibiting proliferation, promoting apoptosis, and remodeling the TME. This study reveals a novel lipid-centric mechanism for PCa intervention using PAC.

Keywords:  Chinmedomics; Lipid metabolism remodeling; Lipidomics; Multi-target mechanism; Phellodendri Amurensis cortex; Prostate cancer

DOI:  https://doi.org/10.1016/j.jep.2025.120674
Mol Cancer Ther. 2025 Oct 03.

Preclinical activity of the DLL3-targeted T cell engager MK-6070 in neuroendocrine prostate cancer.

Sheng-Yu Ku, Nishat Manzar, Maria Mica Garcia, Min Jin Kim, David J Einstein, Steven P Balk, Yasutaka Yamada, Himisha Beltran.

Neuroendocrine prostate cancer is an aggressive variant of prostate cancer with limited therapeutic options. Delta-like ligand 3 (DLL3) is a cell surface protein and therapeutic target expressed in the vast majority of NEPC tumors. The DLL3-targeted T cell activating construct MK-6070 (formerly called HPN328) binds to both DLL3 on tumor cells and CD3 on T cells, as well as serum albumin to extend half-life. A phase 1/2 trial of MK-6070 is currently underway which includes an NEPC cohort (NCT04471727). Here we report the preclinical activity of MK-6070 in prostate cancer models, showing high specificity and anti-tumor activity in DLL3-expressing NEPC models both in vitro and in vivo, with T cell activation and tumor infiltration of T cells after treatment. MK-6070 also demonstrates anti-tumor activity in mixed tumors, impacting DLL3-negative prostate cancer cells after engagement with surrounding DLL3-expressing tumor cells, supporting a potential bystander effect. Overall, these data demonstrate promising activity of MK-6070 in NEPC preclinical models including heterogeneous tumors, supporting the clinical development of MK-6070.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0453
Ther Adv Med Oncol. 2025 ;17 17588359251379416

The future of androgen receptor targeting in prostate cancer: third-generation inhibitors and beyond.

Alice Bernard-Tessier, Natacha Naoun, Solenn Barraud, Ronan Flippot, Cedric Pobel, Macarena Rey, Capucine Baldini, Christophe Massard, Anna Patrikidou, Alina Fuerea, Mario Di Palma, Laurence Albigès, Yohann Loriot, Karim Fizazi.

  The androgen receptor (AR) pathway plays a fundamental role in the treatment of prostate cancer, from the localized stage to metastatic disease, even in castration-resistant prostate cancer (CRPC). Despite the significant benefit for the earlier use of second-generation AR pathway inhibitors (ARPI), treatment resistance is still emerging. A deeper understanding of the biology of ARPI resistance is crucial for developing new therapeutic targets. In this review, we will explore the biology of second-generation ARPI resistance and discuss the evolving landscape of third-generation ARPI and steroid hormone inhibitors, which are shaping the future of prostate cancer therapeutics. Targeting the biosynthesis of steroid precursors with CYP11A1 inhibition, inducing AR degradation with proteolysis-targeting chimera degraders or restoring ARPI sensitivity with EZH2 inhibitors are among the most advanced strategies in development. Alongside these new drugs, AR genomic alterations and particularly AR mutations emerge as a promising biomarker for patient selection. These innovative therapeutics help bring more personalized approaches to patients with prostate cancer, aiming to overcome resistance and improve patient outcomes.

Keywords:  AR alterations; AR-targeted therapy; androgen receptor pathway inhibitor; castration-resistant prostate cancer; drug resistance

DOI:  https://doi.org/10.1177/17588359251379416
Curr Issues Mol Biol. 2025 Sep 22. pii: 782. [Epub ahead of print]47(9):

miR-145-5p and miR-148b-3p Expression Is Inversely Associated with Pten Expression in Prostate Pathologies.

Karla Lizbeth Morales Hernández, Noemí García Magallanes, Marco Alvarez Arrazola, Fred Luque Ortega, Martín Irigoyen Arredondo, Fernando Bergez Hernandez, Eliakym Arambula Meraz.

  Prostate cancer (PCa) represents a significant cause of cancer-associated mortality in the male population worldwide and constitutes a multifactorial disease influenced by genetic and epigenetic factors. Deregulation of genes such as AR and PTEN, as well as alteration in the expression of microRNAs (miRNAs), including miR-145-5p and miR-148b-3p, has been observed in this pathology. This study aimed to explore the correlation between the expression of miR-145-5p, miR-148b-3p, and PTEN in prostate tissue, providing initial insight into their potential interaction in cancer biology. We analyzed 71 samples, comprising 41 from patients with confirmed prostate cancer (PCa group) and 30 from patients with benign prostatic disease (BPD group). Our findings demonstrated a statistically significant association between both miRNAs and the PTEN gene, specifically between miR-148b-3p and PTEN (p = 0.00001) and between miR-145-5p and PTEN (p = 0.0078). These findings support the hypothesis that reduced levels of these miRNAs may be linked to PTEN regulation in prostate pathologies and underscore their potential relevance in PCa biology.

Keywords:  PTEN; correlation; miRNAs; prostate cancer

DOI:  https://doi.org/10.3390/cimb47090782
Biochim Biophys Acta Mol Cell Res. 2025 Sep 30. pii: S0167-4889(25)00167-3. [Epub ahead of print] 120062

Comprehensive analysis of androgen receptor splice variant target gene expression in prostate cancer.

Neele Wüstmann, Julissa Reimann, Julia Vieler, Verena Humberg, Katrin Schlack, Martin Bögemann, Andres Jan Schrader, Christof Bernemann.

  This study aimed to comprehensively analyze AR-V specific target gene expression using a physiological system that simulates the actual situation of AR-FL and AR-V co-appearance in prostate cancer patients. Clinically described AR splice variants AR-V3, AR-V7 and AR-V9 were transfected along with AR-FL in AR-negative prostate cancer PC-3 cells. RNA sequencing analysis showed only slight differences in differentially expressed genes between AR-FL and AR-V co-expressing cells compared to solely AR-FL expressing cells. Immunofluorescence analysis and luciferase assays revealed hormonal dependency of AR-FL, constitutive activity of AR-V7, and ambivalent activity of AR-V9, while AR-V3 showed no activity. Analysis of a set of published target genes showed steady upregulation of EDN2 and FKBP5. Yet, clinical analysis revealed no significant differences in overall survival data in prostate cancer patients. The study challenges the existence of an AR-V specific transcriptome responsible for treatment resistance and tumor progression and highlights the need for further investigation into the molecular mechanism by which AR-V proteins route resistance to ARTA treatment.

Keywords:  Androgen receptor; Androgen receptor splice variants; Androgen receptor targeted agents; Biomarker; Liquid biopsy; Metastatic castration resistant prostate cancer; Predictive; Prognostic; Target genes

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120062
Discov Oncol. 2025 Oct 03. 16(1): 1805

Evaluating the prognosis of prostate cancer through metabolic pathways.

Qiang Su, Yi Hu, Bin Dai.

   BACKGROUND: The pathogenesis of prostate cancer (PCa) is strongly influenced by metabolism. Thus, we explored candidate genes with metabolism-related functions that can be used to predict PCa prognosis.
METHODS: To create a training set and two validation sets, RNA data and clinical parameters were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Risk score (RS) was constructed based on metabolism-related gene signatures. The predictive power of the RS was evaluated. A nomogram related to biochemical recurrence-free survival (BCRFS) was built and evaluated. Finally, an enrichment analysis using Gene Set Enrichment Analysis (GSEA) was performed to identify enriched Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) categories. The Human Protein Atlas (HPA) platform was employed to identify the expression of important genes at the protein level.
RESULTS: Five gene signatures from 860 metabolism-related genes were selected. RS were constructed using the five-gene signatures, which showed high prognostic power for biochemical recurrence (BCR). The nomogram effectively predicted BCRFS. According to GO analysis, DNA damage is primarily associated with genes involved in metabolism. The five-gene signatures were primarily enriched in sulfur metabolic pathways, as analyzed by KEGG. With the progression of prostate cancer malignancy, the expression of HAGHL, and INPP5E also increased.
CONCLUSION: The study establishes a robust, metabolism-based prognostic model for prostate cancer.

Keywords:  Biochemical relapse; Metabolic gene signature; Nomogram; Progression; Prostate cancer

DOI:  https://doi.org/10.1007/s12672-025-03514-y
Cell Cycle. 2025 Sep 29. 1-18

Identification of progression markers for prostate cancer.

Jie Song, Yang Zhou, Harald Hedman, Tommi Rantapero, Maréne Landström.

  TGFβ functions as a tumor suppressor or promoter, depending on the context, making TGFβ a useful predictive biomarker. Genes related to TGFβ signaling and Aurora kinase were tested for their ability to predict the progression risk of primary prostate tumors. Using data from The Cancer Genome Atlas (TCGA), we trained an elastic-net regularized Cox regression model including a minimal set of gene expression, copy number (CN), and clinical data. A multi-step feature selection and regularization scheme was applied to minimize the number of features while maintaining predictive power. An independent hold-out cohort was used to validate the model. Expanding from prostate cancer, predictive models were similarly trained on all other eligible cancer types in TCGA. AURKA, AURKB, and KIF23 were predictive biomarkers of prostate cancer progression, and upregulation of these genes was associated with promotion of cell-cycle progression. Extending the analysis to other TCGA cancer types revealed a trend of increased predictive performance on validation data when clinical features were complemented with molecular features, with notable variation between cancer types and clinical endpoints. Our findings suggest that TGFβ signaling genes, prostate cancer related genes and Aurora kinases are strong candidates for patient-specific clinical predictions and could help guide personalized therapeutic decisions.

Keywords:  AURKA/B; Cancer; KIF23; TGFBR1; prognostic modeling

DOI:  https://doi.org/10.1080/15384101.2025.2563930
Future Oncol. 2025 Oct 03. 1-9

Treatment options in hormone-sensitive prostate cancer: targeting the androgen-sensitive pathway.

Cora N Sternberg, Alicia K Morgans.

  This podcast examines how hormone-sensitive prostate cancer (HSPC) is treated, specifically looking at therapies that target the androgen-sensitive pathway. Identification of patients and the clinical rationale for following different treatment pathways is reviewed, including examination of the current treatment options for both metastatic HSPC (mHSPC) and nonmetastatic HSPC, and consideration of barriers that might exist for optimal treatment. The importance of selecting a treatment strategy that offers control of the disease but allows the patient to maintain their functionality and quality of life is discussed, with an emphasis that, for patients with high-risk biochemical recurrence or mHSPC, combination treatment with androgen deprivation therapy and an androgen receptor pathway inhibitor is the standard of care that should be considered unless contraindicated.

Keywords:  Androgen receptor pathway inhibitors; PSMA PET imaging; hormone-sensitive prostate cancer; prostate neoplasms; quality of life; therapeutics

DOI:  https://doi.org/10.1080/14796694.2025.2561320