bims-meproc 2025-09-14 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–09–14
23 papers selected by
Grigor Varuzhanyan, UCLA

LncRNA HANR promotes the aerobic glycolysis in prostate cancer by stabilizing TPI1.
Prostate cancer with favourable histology is not synonymous with prostate cancer indolence.
Drug targets in prostate cancer: an appetite for KLK2-mediated destruction.
GSK-3 inhibitor induces apoptosis and cell cycle arrest in CD133+/CD44+ prostate cancer cells through modulation of Notch signaling pathway.
Discoidin Domain Receptor 2 (DDR2) Promotes Prostate Cancer Progression in Cooperation with Collagen Remodeling.
Enzalutamide-Resistant STEAP4+ MyoCAF Secrete Phosphatidylcholine to Foster Progression by Activating Stemness in Hormone-Sensitive Prostate Cancer.
Analysis of Microarray and Single-Cell RNA-Seq Finds Gene Co-Expression and Tumor Environment Associated with Extracellular Matrix in Epithelial-Mesenchymal Transition in Prostate Cancer.
Ginsenoside Rh2 repressed the progression of prostate cancer through the mitochondrial damage induced by mitophagy and ferroptosis.
Integration of network toxicology, machine learning and single-cell sequencing reveals the effects of soil pollutants on prostate cancer.
The role of reactive oxygen species in the transformation from prostatitis to prostate cancer: a review.
Plasma metabolites mediate the effects of circulating immune cell phenotypes on prostate cancer: A 2-step Mendelian randomization study.
Cancer-associated fibroblasts-derived exosome PIK3AP1 promotes the malignant progression and immune escape of prostate cancer cells.
Effect of Proton-Pump Inhibitor on Survival in Chinese Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer Receiving Upfront Combinatorial Docetaxel Treatment.
Exploring the Functional Role of Programmed Death-Ligand 1 (PD-L1) in the Castration-Resistant Prostate Cancer Using Transcriptomic Sequencing Analysis.
The need for novel biomarkers in prostate cancer: a UrOP perspective.
Disrupting the interaction between androgen receptor and its coregulator WDR77 delays the growth of treatment-resistant prostate cancer.
Advances in PSMA-Targeted Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer.
Evaluation of potential prognostic significance of JUNB in human prostate cancer: a bioinformatic and histopathological study.
UHMK1 Promotes Prostate Cancer Progression through a Positive Feedback Loop with MTHFD2.
Defining aging-associated factors that increase susceptibility to prostate cancer.
CD63 is a diagnostic marker of prostate cancer and a prognostic marker of biochemical progression following radical prostatectomy.
Urinary Metabolome Study for Monitoring Prostate Cancer Recurrence Following Radical Prostatectomy.
Prostate cancer: MRI shakeup could be cheaper and faster, study finds-but experts warn of potential overdiagnosis.

Exp Cell Res. 2025 Sep 06. pii: S0014-4827(25)00344-1. [Epub ahead of print]452(1): 114744

LncRNA HANR promotes the aerobic glycolysis in prostate cancer by stabilizing TPI1.

Ziye Wang, Xiaoguang Li, Zhengdao Liu, Yang Du, Tao Wu.

  Prostate cancer (PCa) is a type of malignancy that originates in the prostate gland, often characterized by uncontrolled cell growth and potential metastasis. Long non-coding RNAs (lncRNAs) play crucial regulatory roles in the progression of prostate cancer, potentially facilitating tumor growth and metastasis via mechanisms that involve the enhancement of aerobic glycolysis. This study aimed to investigate the functional role of lncRNA HANR in prostate cancer progression. Bioinformatics analysis and experimental validation revealed a significant up-regalation of HANR in prostate cancer tissues, in comparison to adjacent normal tissues. Functional studies demonstrated that silencing HANR inhibited prostate cancer cells proliferation, migration, invasion, and glycolysis. While HANR overexpression promoted prostate cancer cells proliferation, invasion, and glycolysis. Mechanistically, HANR interacts with triosephosphate isomerase 1 (TPI1), a key glycolytic enzyme, to promote glycolysis and tumor growth. Silencing HANR or TPI1 reduced prostate tumor growth both in vitro and in vivo. In conclusion, our findings suggest that the HANR-TPI1 axis plays a crucial role in the progression of prostate cancer and may represent a novel biomarker and therapeutic target for aggressive prostate cancer, given its role in enhancing aerobic glycolysis and facilitating tumorigenesis in prostate cancer cells.

Keywords:  Aerobic glycolysis; HANR; Proliferation; Prostate cancer; TPI1

DOI:  https://doi.org/10.1016/j.yexcr.2025.114744
Histopathology. 2025 Sep 09.

Prostate cancer with favourable histology is not synonymous with prostate cancer indolence.

Rajal B Shah, Gladell P Paner, Glen Kristiansen.



Keywords:  favourable histology; indolence; prostate cancer; unfavourable histology

DOI:  https://doi.org/10.1111/his.15556
Clin Cancer Res. 2025 Sep 09.

Drug targets in prostate cancer: an appetite for KLK2-mediated destruction.

Steven Blinka, Evan Y Yu.

Human Kallikrein 2 (KLK2) is a prostate cancer tissue specific protein that is regulated by androgen receptor (AR) signaling. KLK2 was not previously recognized as a therapeutic target as it is secreted. It has now been demonstrated that KLK2 is expressed on the cell surface and targetable by various methodologies.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-2546
Mol Biol Rep. 2025 Sep 11. 52(1): 892

GSK-3 inhibitor induces apoptosis and cell cycle arrest in CD133+/CD44+ prostate cancer cells through modulation of Notch signaling pathway.

Eda Acikgoz, Berrin Ozdil, Gulperi Oktem, Huseyin Aktug, Murat Cetin Ragbetli, Cafer Tas.

   BACKGROUND: Treatment of advanced prostate cancer (PCa) is a major challenge due to the persistence of drug-resistant cancer stem cells (CSCs), which are mainly responsible for metastasis and recurrence. Therefore, the key to achieve an effective treatment approach in PCa is through the development of strategies targeting CSCs. GSK-3, also known as a moonlight kinase, is associated with multiple signaling pathways involved in embryonic development and cancer, including Wnt/β-catenin, Sonic hedgehog, and Notch. Strong evidence suggests that pharmacological inhibition of GSK-3 can eliminate the prostate cancer stem/progenitor-like population. The present study aims to evaluate the effects of GSK-3 inhibitor IX on CD133+/CD44+ cells isolated from DU145 cell line.
METHODS AND RESULTS: Following treatment with various concentrations of GSK-3 inhibitor IX, we assessed cell viability, apoptosis, cell cycle, and multicellular tumor spheroids formation capacity. Furthermore, expression levels of components in the Notch signaling pathway due to GSK-3 inhibition were examined by immunofluorescence staining. The results revealed that GSK-3 inhibitor IX exhibited strong anti-proliferative effects by inducing apoptotic cell death, causing G0/G1 phase arrest of CD133+/CD44+ cells. The number and size of the spheroids decreased significantly upon treatment with GSK-3 inhibitor IX. Furthermore, GSK-3 inhibition resulted in a marked reduction in the expression of Notch1 and Delta, which are important components of the Notch signaling pathway.
CONCLUSION: Together, our data demonstrated that GSK-3 inhibitor IX effectively eliminated CD133+/CD44+ cells by suppressing the Notch signaling pathway, which is critical for CSC maintenance and survival, and may offer a promising therapeutic strategy for prostate cancer treatment with further research.

Keywords:  Apoptosis; Cancer stem cell; Cell cycle; GSK-3; Notch; Prostate cancer

DOI:  https://doi.org/10.1007/s11033-025-10977-3
Acta Histochem Cytochem. 2025 Aug 28. 58(4): 143-152

Discoidin Domain Receptor 2 (DDR2) Promotes Prostate Cancer Progression in Cooperation with Collagen Remodeling.

Mikoto Sagehashi, Kiyoshi Takagi, Ai Sato, Mio Yamaguchi-Tanaka, Yasuhiro Miki, Akihiro Ito, Takashi Suzuki.

  Prostate cancer is one of the most common malignancies in men and remodeling of extracellular collagen, especially collagen type I immensely contributes to the progress of prostate cancer. Discoidin domain receptor 2 (DDR2) is a receptor of collagen type I and transmits intracellular signaling in not only normal cells but also malignant cells, facilitating tumor progression. However, clinical and biological significance of DDR2 has not been well examined in prostate cancer. We therefore immunolocalized DDR2 and collagen type I in 117 prostate carcinoma tissues and correlated their immunoreactivity with clinicopathological characteristics of prostate cancer. We also conducted in vitro experiments using human prostate cancer cell lines to confirm the findings from immunohistochemical study. DDR2 immunoreactivity was positively associated with an aggressive phenotype of prostate cancer, partially in association with dense collagen I tissues which consisted of thin fibers. In addition, DDR2 immunoreactivity was significantly correlated with adverse clinical outcomes of prostate cancer. In vitro experiments revealed that DDR2 promoted proliferation and migration of PC-3 and DU-145 prostate cancer cell lines. It is therefore speculated that DDR2 promoted prostate cancer progression by interacting with collagen I, serving as a potent prognostic factor in prostate cancer.

Keywords:  collagen type I; discoidin domain receptor 2 (DDR2); immunohistochemistry; prognosis; prostate cancer

DOI:  https://doi.org/10.1267/ahc.25-00009
Adv Sci (Weinh). 2025 Sep 08. e10602

Enzalutamide-Resistant STEAP4+ MyoCAF Secrete Phosphatidylcholine to Foster Progression by Activating Stemness in Hormone-Sensitive Prostate Cancer.

Wenhao Wang, Jing Zhao, Tiewen Li, Guangjian Fan, Jianong Zhang, Chenghao Zheng, Zhiwen Xie, Yu Zhang, Chengling Feng, Tianyu Cao, Jianyin Li, Guomin Ju, Di Cui, Shujie Xia, Bangmin Han.

  Despite the expanding clinical application of second-generation anti-androgens like enzalutamide (ENZ) in hormone-sensitive prostate cancer (HSPC), therapeutic resistance culminating in castration-resistant prostate cancer (CRPC) persists as an unresolved clinical crisis. Through comprehensive single-cell transcriptomic profiling of ENZ-naïve and ENZ-treated tumors, an expansion of ENZ-resistant myofibroblastic cancer-associated fibroblast (designated STEAP4+ myoCAF) is identified that correlates with adverse clinical outcomes. Strikingly, STEAP4+ myoCAF demonstrated intrinsic ENZ resistance through a mechanistically novel pathway involving transcription factor binding to IGHM enhancer 3 (TFE3)-mediated autophagy activation. Integrated lipidomic and functional analyses revealed that TFE3 activation drives phosphatidylcholine overproduction via direct upregulation of phosphate cytidylyltransferase 1A (PCYT1A), establishing a tumor-promoting feedforward loop. The resultant phospholipid-rich microenvironment activates an HSP90/HIF1A signaling axis in malignant epithelial cells, fueling cancer stemness and therapeutic escape. These findings position the STEAP4+ myoCAF-TFE3/tumor-HIF1A axis as a master regulator of anti-androgen resistance, offering clinically actionable targets to extend treatment efficacy in advanced prostate cancer.

Keywords:  autophagy; cancer‐associated fibroblasts; enzalutamide; phosphatidylcholine; prostate cancer; stemness

DOI:  https://doi.org/10.1002/advs.202510602
Int J Mol Sci. 2025 Sep 03. pii: 8575. [Epub ahead of print]26(17):

Analysis of Microarray and Single-Cell RNA-Seq Finds Gene Co-Expression and Tumor Environment Associated with Extracellular Matrix in Epithelial-Mesenchymal Transition in Prostate Cancer.

Ali Shakeri Abroudi, Mahtab Mashhouri Moghaddam, Danial Hashemi Karoii, Melika Djamali, Hossein Azizi, Thomas Skutella.

  A complex and gradual process, the epithelial-mesenchymal transition (EMT) occurs both during embryonic development and tumor progression. Cells undergo a transition from an epithelial to a mesenchymal state throughout this process. More and more evidence points to EMT as a cause of increased metastatic spread of prostate cancer (PCa), along with stemness enhancement and therapy resistance. Here, we used bioinformatic methods to analyze gene expression microarray data, single-cell RNA sequencing, oncogenes, and tumor suppressor genes (TSGs) in order to reconstruct the network of differentially expressed genes (DEGs) involved in the epithelial-mesenchymal transition with PCa. No prior study has documented this sort of analysis. We next validated our results using data from the Cancer Genome Atlas (TCGA), which included microarray and single-cell RNA sequencing. Potentially useful in PCa diagnosis and treatment are extracellular matrix in epithelial-mesenchymal transition genes, including ITGBL1, DSC3, COL4A6, ANGPT1, ARMCX1, MICAL2, and EPHA5. In this study, we aimed to shed light on the molecular characteristics and pathways of DEGs in PCa, as well as to identify possible biomarkers that are important in the development and advancement of this cancer. These insights have important implications for understanding prostate cancer progression and for the development of therapeutic strategies targeting ECM-mediated pathways.

Keywords:  cell–cell communication; epithelial–mesenchymal; microarray; prostate cancer; stemness

DOI:  https://doi.org/10.3390/ijms26178575
Front Oncol. 2025 ;15 1633891

Ginsenoside Rh2 repressed the progression of prostate cancer through the mitochondrial damage induced by mitophagy and ferroptosis.

Zhen He, Jianxi Shi, Bing Zhu, Zhentao Tian, Zhihong Zhang, Changwen Zhang.

   Introduction: Prostate cancer (PC), the most common male genitourinary malignancy and second leading cause of global cancer deaths in men, frequently progresses to lethal castration-resistant PC (CRPC). Ginsenoside Rh2 (GRh2), a ginseng-derived bioactive compound, exhibits antitumor potential, but its efficacy and mechanisms in PC remain unclear.
Methods: PC3 cells were treated with GRh2 to assess proliferation (IC50 calculation), migration, and invasion. Mitochondrial function (membrane potential, ROS, ATP/ADP), mitophagy markers (PINK1/Parkin, VDAC1/TOM20, autophagosomes), and ferroptosis indicators (lipid ROS, MDA, Fe2+, GSH, SLC7A11/GPX4) were evaluated. Specific inhibitors (Mdivi-1 for mitophagy, Fer-1 for ferroptosis) validated mechanistic causality. Subcutaneous xenograft models in nude mice assessed in vivo efficacy.
Results: GRh2 potently inhibited PC3 cell proliferation (IC50 = 19.3 μg/mL), migration, and invasion. It induced mitochondrial dysfunction (depolarized membrane, elevated ROS, disrupted ATP/ADP) and activated mitophagy, evidenced by upregulated PINK1/Parkin, reduced VDAC1/TOM20, and autophagosome accumulation. Concurrently, GRh2 triggered ferroptosis via lipid ROS accumulation, increased MDA/Fe2+, GSH depletion, and SLC7A11/GPX4 downregulation. All effects were reversed by Mdivi-1 or Fer-1, confirming pathway-specific causality. In vivo, GRh2 significantly suppressed tumor growth.
Discussion: This study provides the first evidence that GRh2 exerts synergistic antitumor effects in PC through dual induction of mitophagy-associated mitochondrial damage and ferroptosis. The reversibility of both pathways by specific inhibitors establishes a causal mechanistic framework. GRh2 thus represents a multifaceted therapeutic agent against PC by targeting mitochondrial integrity.

Keywords:  Chinese medicine; PC; ferroptosis; ginsenoside Rh2; mitochondrial damage; mitophagy

DOI:  https://doi.org/10.3389/fonc.2025.1633891
Ecotoxicol Environ Saf. 2025 Sep 08. pii: S0147-6513(25)01355-7. [Epub ahead of print]303 119010

Integration of network toxicology, machine learning and single-cell sequencing reveals the effects of soil pollutants on prostate cancer.

Zhiyu Liu, Yuqi Li, Juan Wang, Yang Zeng, Qilong Wu, Xinyao Zhu, Tao Zhou, Qingfu Deng.

   BACKGROUND: Prostate cancer (PRAD) is a common malignancy in men, and exposure to soil pollutants may contribute to its development. And exposure to soil pollutant has been linked to its development, as well as to other diseases including cardiovascular disorders, neurological conditions, and additional cancers.
METHODS: This study integrates network toxicology, machine learning, and advanced technologies to investigate the mechanisms through which soil pollutants affect prostate cancer. Network toxicology was used to identify targets and signaling pathways associated with soil pollutants. Target prediction of soil pollutants was performed through SwissTargetPrediction and the Similarity Ensemble Approach (SEA). Prostate cancer-associated target genes were obtained from the Genecards and OMIM databases. Protein-protein interaction analysis further identified key regulatory molecules. Then a predictive model was constructed with 101 machine learning algorithms, identified risk target molecules and assessed the relationship between soil pollutants and prostate cancer risk. Single-cell sequencing examined the expression profiles of these targets in prostate cancer cell types. Molecular docking simulations evaluated the binding affinities between pollutants and target proteins to explore potential molecular mechanisms.
RESULTS: Ten soil pollutants were analyzed, including dibutyl phthalate (DBP), dioctyl phthalate (DOP), dimethyl phthalate (DMP), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), methyl ethyl ketone (MEK), toluene (TOL), zearalenone (ZEN), ochratoxin A (OTA), and deoxynivalenol (DON). Integration of multiple databases identified 242 potential targets, and protein-protein interaction analysis revealed key regulatory molecules. A prognostic risk model identified 26 risk target molecules. Single-cell sequencing demonstrated their expression profiles in prostate cancer. Kaplan-Meier, univariate, and multivariate Cox regression analyses revealed independent prognostic significance for DNMT1 and MTOR. Molecular docking confirmed that most soil pollutants bind strongly to DNMT1 and MTOR, suggesting disruption of related signaling pathways. Furthermore, experiments were conducted to explore the relationship between soil pollutants and target proteins.
CONCLUSIONS: Various analytical methods to elucidate mechanisms by which soil pollutants contribute to prostate cancer through interactions with key molecular targets DNMT1 and mTOR. These findings inform the prevention and treatment of environmentally related cancers and provide novel insights into the molecular connection between soil pollutants and prostate cancer, and laying the groundwork for preventive and intervention strategies targeting environmentally related cancers.

Keywords:  Machine learning; Molecular docking; Network toxicology; Prostate cancer (PRAD); Single-cell sequencing; Soil pollutants

DOI:  https://doi.org/10.1016/j.ecoenv.2025.119010
Front Immunol. 2025 ;16 1662792

The role of reactive oxygen species in the transformation from prostatitis to prostate cancer: a review.

Kaihua Tang, Zhipeng Jiang, Wen Luo, Jing Li, DeCan Liang, Lei Liu, ZongMin Long.

  In the study of prostate diseases, the microenvironment associated with chronic prostatitis is characterized by abnormal activation of immune cells, leading to excessive accumulation of pro-inflammatory factors and an imbalance in the antioxidant defense system. This results in the overproduction of reactive oxygen species (ROS) and the subsequent triggering of oxidative stress. Oxidative stress persistently disrupts the homeostasis of prostate tissue through various mechanisms, including the damage to biomacromolecules, the regulation of inflammatory pathways, and the induction of apoptosis. ROS, as natural products of cellular metabolism, exhibit a dual role in biological systems. They are involved in the regulation of physiological signals while also possessing the potential to induce pathological damage. Further research indicates that during the occurrence and progression of prostate cancer (PCa), the gradually increasing ROS in the tumor microenvironment can activate cancer-related signaling pathways, induce Deoxyribonucleic Acid (DNA) mutations, and promote the abnormal proliferation of tumor cells. ROS are widely recognized as pivotal molecules that connect chronic inflammation to carcinogenesis. Currently, the mechanisms by which ROS mediate the cross-linking of inflammatory and carcinogenic signaling pathways during the progression from chronic prostatitis to PCa remain inadequately understood. This review systematically analyzes the multifaceted mechanisms of ROS in inflammation-induced carcinogenesis. It preliminarily elucidates the inflammatory origins of PCa and explores early intervention strategies based on the regulation of oxidative stress. The goal is to provide novel potential targets and a theoretical foundation for the comprehensive prevention and treatment of chronic prostatitis and PCa.

Keywords:  inflammation-cancer; oxidative stress; prostate cancer; prostatitis; reactive oxygen species; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1662792
Medicine (Baltimore). 2025 Sep 05. 104(36): e44282

Plasma metabolites mediate the effects of circulating immune cell phenotypes on prostate cancer: A 2-step Mendelian randomization study.

Wenjie Zhou, Jiawei Ding, Yan Shen, Fanyu Huang, Danfeng Xu.

  Prior research suggested the potential correlation between circulating immune cell phenotypes and prostate cancer (PCa). However, it remains unclear whether the correlation can be mediated by plasma metabolites. We performed a bidirectional 2-sample, 2-step Mendelian randomization (MR) study mainly utilizing the inverse variance weighted method to examine the causal role of circulating immunophenotypes on PCa and explore the mediation effect of plasma metabolites in the pathway from immunophenotypes to PCa. MR analyses revealed that 7 circulating immune cell phenotypes and 9 plasma metabolites were significantly related to the risk of PCa. Notably, the mediation MR analysis revealed that X-12100 levels accounted for 10.5% of the decreased risk of PCa associated with CD4 + CD8dim AC in TBNK panel, and X-24418 levels accounted for 11.8% of the elevated risk of PCa related to FSC-A on granulocyte in cDC panel. Our study established a causal relationship between immunophenotypes and PCa, and unveiled the mediating role of plasma metabolites in this association. Meanwhile, we emphasized the notable impact of the immune-metabolite axis on PCa, and immune cells may promote or inhibit tumor progression by influencing metabolite levels, providing a novel insight for studying the pathogenic mechanisms of PCa.

Keywords:  Mendelian randomization; immune cell phenotypes; mediation analysis; plasma metabolites; prostate cancer

DOI:  https://doi.org/10.1097/MD.0000000000044282
Pathol Res Pract. 2025 Sep 04. pii: S0344-0338(25)00402-9. [Epub ahead of print]275 156209

Cancer-associated fibroblasts-derived exosome PIK3AP1 promotes the malignant progression and immune escape of prostate cancer cells.

Tan Li, Cheng Yi, Zhendong Xiang, Xiangyun You, Junfeng Yu.

   BACKGROUND: Prostate cancer (PCa) is a common malignant cancer. Cancer-associated fibroblasts (CAFs) play an important role in occurrence and development of tumors. B-cell adapter protein (PIK3AP1) is related to cell growth, inhibits cell apoptosis and mediates tumor therapy. Thereby, this study aims to explore the role and mechanism of CAFs exosomes and PIK3AP1 in PCa.
METHODS: Normal fibroblasts (NFs), CAFs, and exosomes were characterized by morphology observation and western blot. The proliferation, migration, invasion, and cell viability were examined by 5-Ethynyl-2'-deoxyuridine (EdU), transwell, and cell counting kit-8 (CCK8) assays, respectively. Proliferation and apoptosis of CD8+T cells were tested using flow cytometry. Gene expression was analyzed using qRT-PCR and western blot. Animal experiments were utilized to analyze the role of CAF-derived exosome PIK3AP1 in vivo.
RESULTS: CAFs-derived exosomes promoted the PCa cell proliferation, migration, invasion, cell viability, and immune escape. PIK3AP1 was up-regulated in CAFs and PCa cells and related to tumor immune escape. PIK3AP1 facilitated the malignant behavior of PCa and the immune escape in vivo and in vitro. CAFs-derived exosome promoted PCa progression and immune escape via carrying PIK3AP1.
CONCLUSIONS: CAFs-derived exosomes promote the malignant behavior and immune escape of PCa cells by PIK3AP1.

Keywords:  CAFs; Exosomes; Immune escape; PIK3AP1; Prostate cancer

DOI:  https://doi.org/10.1016/j.prp.2025.156209
Cancers (Basel). 2025 Sep 01. pii: 2879. [Epub ahead of print]17(17):

Effect of Proton-Pump Inhibitor on Survival in Chinese Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer Receiving Upfront Combinatorial Docetaxel Treatment.

Chris Ho-Ming Wong, Jamie Tsun Chiu, Ivan Ching-Ho Ko, David Ka-Wai Leung, Brian Siu, Cheuk-Kin Kevin Cheng, Yung-Yung Joycelyn Lim, Hiu Tung Mok, Chun-Fai Brian Kwok, Cheuk Yi Tang, Steven Chi-Ho Leung, Kang Liu, Peter Ka-Fung Chiu, Jeremy Yuen-Chun Teoh, Chi Fai Ng.

  Prostate cancer is the second most commonly found malignancy for men worldwide, with its prevalence increasing with age [...].

Keywords:  androgen deprivation therapy (ADT); docetaxel; drug–drug interaction; metastatic hormone-sensitive prostate cancer (mHSPC); prostate cancer; proton-pump inhibitor (PPI)

DOI:  https://doi.org/10.3390/cancers17172879
Cancer Med. 2025 Sep;14(17): e71225

Exploring the Functional Role of Programmed Death-Ligand 1 (PD-L1) in the Castration-Resistant Prostate Cancer Using Transcriptomic Sequencing Analysis.

Lin Zhong, Pengxin Zhang, Jialin Ji, Jun Mao, Lianhong Li.

   BACKGROUND: Prostate cancer is one of the principal malignancies threatening human health, and the development of castration resistance often constitutes a major cause of treatment failure in its management.
METHODS: To elucidate the potential association between programmed death-ligand 1 (PD-L1) and castration resistance in prostate cancer, we analyzed the expression levels of PD-L1 in both primary prostate cancer tissues and castration-resistant prostate cancer (CRPC) specimens as well as in corresponding cell lines by using western blots and immunohistochemistry. Then, we explored the specific mechanisms through transcriptomic sequencing technology.
RESULTS: Our findings revealed that, compared to adjacent non-cancerous tissue, PD-L1 expression was unexpectedly lower in primary prostate cancer but notably elevated in CRPC tissues and cells. In CRPC cell lines where PD-L1 was knocked down, a significant suppression of proliferation, invasion, and migration capabilities was observed. By employing next-generation sequencing technology, we investigated the impact of PD-L1 knockdown on intracellular signaling pathways in castration-resistant cells. The results demonstrated that PD-L1 knockdown led to alterations in gene expression within several signaling pathways, including those involved in cell surface interactions, regulation of natural killer cell activity, and sodium channel regulatory activity. We further elucidated through experimentation that PD-L1 contributes to tumor progression in CRPC by modulating the expression of SCUBE1. More intriguingly, PD-L1 knockdown also appeared to induce changes at the level of alternative splicing in multiple genes.
CONCLUSIONS: PD-L1 is upregulated in CRPC and can modulate the expression of multiple tumor-associated genes in CRPC cells. Finally, we found that PD-L1 contributes to tumor progression in CRPC by modulating the expression of SCUBE1. This study provides a theoretical basis for understanding the intracellular signaling mediated by PD-L1 and offers valuable insights into the mechanisms underlying castration resistance in prostate cancer.

Keywords:  CRPC; PD‐L1; altinative splicing; prostate cancer; transcriptomic sequencing

DOI:  https://doi.org/10.1002/cam4.71225
Arch Ital Urol Androl. 2025 Sep 11. 14279

The need for novel biomarkers in prostate cancer: a UrOP perspective.

Guglielmo Mantica, Stefano Alba, Andrea Alfarone, Umberto Capitanio, Donato Dente, Carlo Giulioni, Carmelo Morana, Serena Maruccia, Gabriella Mirabile, Gennaro Musi, Mauro Ragonese, Mauro Silvani, Antonio Tufano, Angelo Cafarelli, Alessandro Calarco, Ottavio De Cobelli, Ferdinando De Marco, Giovanni Ferrari, Giuseppe Mario Ludovico, Stefano Pecoraro, Domenico Tuzzolo, Renzo Colombo, Nazareno Suardi, Rosario Leonardi.

Dear Editor, Prostate cancer (PCa) remains one of the most common malignancies among men worldwide, representing a major healthcare burden both in terms of morbidity and economic cost...

DOI: https://doi.org/10.4081/aiua.2025.14279
Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01006-X. [Epub ahead of print]44(9): 116235

Disrupting the interaction between androgen receptor and its coregulator WDR77 delays the growth of treatment-resistant prostate cancer.

Ujjwal R Dahiya, Sangeeta Kumari, Nidhi Singh, Chitra Rawat, Eduardo Cortes, Yara Ghanem, Eva Corey, Scott M Dehm, Belinda Willard, Mohammed Alshalalfa, Elai Davicioni, Jesse McKenney, Christopher Weight, Samuel C Haywood, Song Liu, Tao Liu, Hannelore V Heemers.

  Continued reliance on the androgen receptor (AR) after androgen deprivation therapy (ADT) fails causes 35,000 American prostate cancer (CaP) deaths annually. Targeting the AR's transcriptional activity could overcome this acquired resistance, but has been challenging. We demonstrate the therapeutic potential of disrupting interactions between the AR and its coregulator WDR77. WDR77 stimulated CaP growth, and its overexpression was associated with worse patient survival. AR and WDR77 cistromes overlapped considerably, and AR- and WDR77-bound genes correlated with aggressive CaP features. Direct WDR77-AR interaction occurred, which, when disrupted, prevented AR-WDR77 complex formation, reduced AR DNA-binding and AR-dependent gene expression, and decreased cell proliferation to the same extent as ADT. Such interference inhibited cell growth by ADT-resistant AR action and after ADT-resistance without impacting AR-negative CaP or benign cells. Blocking AR-WDR77 cooperation also delayed the growth of organoids from patient-derived xenografts and fresh CaP specimens. Disrupting coregulator control over AR action may thus improve survival from ADT-resistant CaP.

Keywords:  CP: Cancer; CP: Molecular biology; MEP50; androgen deprivation therapy; androgens; antiandrogens; castration; hormonal therapy; hormones; methylosome; transcription; treatment resistance

DOI:  https://doi.org/10.1016/j.celrep.2025.116235
Cancer Manag Res. 2025 ;17 1859-1869

Advances in PSMA-Targeted Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer.

Jie Wang, Hui Yuan, Jianan Xu, Chongyi Yang.

  Prostate cancer (PCa) is the most common tumor for men in the genital system. Despite several new therapies approved in the past decades, 34,700 patients die on a regular basis in 2023 in America. Recently radioisotopic therapies have shown the delightful results in the PCa treatment, which made FDA approved lutetium-177 for adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castrate-resistant prostate cancer (mCRPC). Many other clinical trials are also in progress in various settings. Both monotherapy and combination studies are underway. However, because of several limitations existed in these clinical trials and alarmed long-term nephrotoxicity of PSMA-targeted therapy, we should be more prudent to this therapy. In this review, we evaluates the evolving clinical and preclinical landscape of PSMA-targeted therapy, as well as the potential biomarkers for evaluating the therapeutic response.

Keywords:  actinium-225; lutetium-177; prostate cancer; prostate-specific membrane antigen; radioligand therapy

DOI:  https://doi.org/10.2147/CMAR.S538367
J Pathol Transl Med. 2025 Sep 08.

Evaluation of potential prognostic significance of JUNB in human prostate cancer: a bioinformatic and histopathological study.

Noha R Noufal, Einas M Yousef, Mohamed Taha.

   Background: Prostate cancer is one of the most common malignancies in males worldwide. Serum prostate-specific antigen is a frequently employed biomarker in the diagnosis and risk stratification of prostate cancer; however, it is known for its low predictive accuracy for disease progression. New prognostic biomarkers are needed to distinguish aggressive prostate cancer from low-risk disease. This study aimed to identify and validate potential prognostic biomarkers of prostate cancer.
Methods: Two prostate cancer datasets from the Gene Expression Omnibus were analyzed to identify differentially expressed genes between benign prostatic hyperplasia (BPH) and prostatic carcinoma. Immunohistochemistry was used to evaluate the JUNB proto-oncogene, a subunit of the AP-1 transcription factor (JUNB), in 70 prostate cancer patients and 10 BPH samples.
Results: Our findings showed that JUNB was significantly enriched in prostate cancer-related pathways and biological processes. JUNB expression was considerably higher in prostatic adenocarcinoma patients than in BPH patients. Regarding JUNB expression in prostate cancer cases, lower levels of JUNB expression were associated with higher grades of prostatic adenocarcinoma. Lower JUNB expression was associated with a higher risk of prostatic adenocarcinoma progression and shorter overall survival.
Conclusions: These results suggest that JUNB is a promising prognostic biomarker and a potential tumor suppressor in prostate cancer.

Keywords:  Benign prostatic hyperplasia; Computational biology; Immunohistochemistry; JUNB; Prostatic neoplasms

DOI:  https://doi.org/10.4132/jptm.2025.06.06
Oncol Res. 2025 ;33(9): 2331-2351

UHMK1 Promotes Prostate Cancer Progression through a Positive Feedback Loop with MTHFD2.

Chi Zhang, Xi Huang, Cheng Hu, Bowen Tang, Jianjie Wu, Zhuolun Sun, Weian Zhu, Xiangfu Zhou, Hengjun Xiao, Hua Wang.

   Background: U2AF homology motif kinase 1 (UHMK1) has been associated with RNA processing and protein phosphorylation, thereby influencing tumor progression. The study aimed to explore its regulatory mechanisms and biological functions in human prostate cancer (PCa).
Methods: In this study, we systematically evaluated the expression and prognostic significance of UHMK1 in public databases, followed by validation through immunohistochemistry (IHC) in PCa specimens. Both gain-of-function and loss-of-function experiments were conducted to elucidate the role of UHMK1 in vitro and in vivo. Additionally, a series of molecular and biochemical assays were performed to investigate the regulatory mechanisms underlying UHMK1 activity.
Results: Our findings revealed that UHMK1 expression was significantly upregulated in PCa tissues and correlated with poor patient prognosis, as demonstrated by analysis of public datasets and confirmed by immunohistochemical staining. Functional studies showed that UHMK1 depletion suppressed tumor cell proliferation and metastasis, while its overexpression promoted these processes. Mechanistically, we identified that UHMK1 phosphorylates nuclear receptor coactivator 3 (NCOA3), which subsequently activates activating transcription factor 4 (ATF4) to upregulate methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) transcription. Interestingly, MTHFD2 was found to reciprocally enhance UHMK1 expression, establishing a positive feedback loop.
Conclusions: In conclusion, our data suggest that the UHMK1-MTHFD2 axis forms a positive feedback loop that drives PCa progression. Targeting this loop represents a promising therapeutic strategy for restraining prostate cancer development and progression.

Keywords:  Cancer progression; U2AF Homology Motif Kinase 1 (UHMK1); methylenetetrahydrofolate dehydrogenase 2 (MTHFD2); positive feedback loop; prostate cancer (PCa)

DOI:  https://doi.org/10.32604/or.2025.065119
Endocr Relat Cancer. 2025 Sep 08. pii: ERC-25-0026. [Epub ahead of print]

Defining aging-associated factors that increase susceptibility to prostate cancer.

Shile Zhang, Ernie Lee, Sachi Bopardikar, Andrew S Goldstein.

Age is a major risk factor for a range of diseases including prostate cancer. Understanding how age influences the susceptibility of normal prostate epithelial cells to cancer initiation is complicated by the fact that aging affects all tissues in the body. Assessing how various aging mechanisms influence the prostate epithelium is a necessary step to determine the critical factors associated with aging that increase prostate cancer risk. Here, we take a broad view of both prostate epithelial cell-intrinsic and cell-extrinsic factors that change with age and are likely to contribute to age-related risk of prostate tumorigenesis. For each factor, we discuss the impact of these age-related changes on cancer risk. We highlight important areas where additional research is required to help decipher the specific age-associated changes that contribute to prostate cancer initiation. Finally, we address the potential impact of various therapeutic interventions on aging phenotypes and cancer risk.

DOI: https://doi.org/10.1530/ERC-25-0026
Histol Histopathol. 2025 Sep 08. 18981

CD63 is a diagnostic marker of prostate cancer and a prognostic marker of biochemical progression following radical prostatectomy.

Elisabeth Dingendorf, Marit Bernhardt, Isabella Federica Bollen, Tobias Kreft, Anna Katrin Scherping, Xiaolin Zhou, Manuel Ritter, Jörg Ellinger, Carsten Stephan, Glen Kristiansen.

AIMS: We aimed to analyze CD63, a cell surface protein that has been associated with tumor aggressiveness in several cancers, including breast, colorectal, and lung cancer, as well as melanoma, in prostate cancer.
METHODS: CD63 expression was analyzed immunohistochemically in a cohort of primary prostate cancers from 281 patients. The results were correlated with clinico-pathologic parameters, including biochemical recurrence. In addition, CD63 expression in 251 of the 281 patients with prostate cancer was compared with CD63 expression in matched benign tissue samples (490 tissue samples). The analysis was performed automatically using the open-source software QuPath© and tested for statistical significance. For comparison with the diagnostic markers AMACR and GOLPH2, CD63 was analyzed in an additional cohort of 198 Prostate cancers.
RESULTS: CD63 expression was found in 100% of prostate cancer cases and benign tissue spots. Increased CD63 expression was significantly associated with higher tumor stage (pT), tumor grade (ISUP), as well as shorter progression-free survival (PFS). Compared with the CD63 intensity of benign tissue, expression in tumor tissue was higher in >80% of cases. In addition, combining the expression of CD63 and AMACR, positivity reached 97.2%, making CD63 a promising diagnostic biomarker in challenging cases.
CONCLUSIONS: CD63 is commonly overexpressed in prostate cancer, and higher levels are associated with earlier biochemical tumor progression; hence, CD63 is a promising diagnostic and prognostic biomarker in primary prostate cancer.

DOI: https://doi.org/10.14670/HH-18-981
Cancers (Basel). 2025 Aug 24. pii: 2756. [Epub ahead of print]17(17):

Urinary Metabolome Study for Monitoring Prostate Cancer Recurrence Following Radical Prostatectomy.

Sabur Badmos, Elizabeth Noriega Landa, Kiana L Holbrook, George E Quaye, Xiaogang Su, Wen-Yee Lee.

   BACKGROUND/OBJECTIVES: Prostate cancer (PCa) is the most common cancer among males. Approximately 20-40% of patients with clinically localized PCa will present with a biochemical recurrence after a radical prostatectomy (RP), while some will present with recurrent metastasis. Monitoring the disease post-treatment is crucial for detecting a potential cancer recurrence early. Urinary volatile organic compounds (VOCs) have shown potential to detect PCa. However, their application in disease monitoring remains unexplored.
METHODS: A total of 165 urine samples were collected from male adults with biopsy-designated PCa-positive results before (n = 55) and after a RP (n = 55), and with biopsy-designated PCa-negative diagnosis (n = 55). The post-RP cohort was subdivided into three groups based on their health status after surgery as recovered healthy, biochemical recurrence, and recurrent metastasis. VOCs in the urine samples were extracted by stir bar sorptive extraction and analyzed using gas chromatography and mass spectrometry. We explored the use of metabolomics and a machine learning algorithm tool to investigate the potential of using VOCs for differentiating PCa diagnoses before and after the RP procedure with different outcomes.
RESULTS: Over 100 potential VOCs were identified to differentiate PCa patients before and after a RP, and those with biochemical recurrence and recurrent metastasis.
CONCLUSIONS: Urinary VOCs are promising biomarkers that could be used to differentiate PCa patients pre- and post-RP. The findings from this research provide preliminary insights and could aid future investigations in developing tools for PCa patients after treatment. The absence of a validation cohort limits the reproducibility and translational impact of these findings; therefore, the results should be considered exploratory and require confirmation in larger, independent cohorts.

Keywords:  GC-MS; PLS-DA; VOCs; biochemical recurrence; metastatic recurrence; prostate cancer diagnosis; radical prostatectomy; urinary biomarkers; volatile organic compounds

DOI:  https://doi.org/10.3390/cancers17172756
BMJ. 2025 Sep 12. 390 r1926

Prostate cancer: MRI shakeup could be cheaper and faster, study finds-but experts warn of potential overdiagnosis.

Kate Bowie.

DOI: https://doi.org/10.1136/bmj.r1926