bims-meproc 2025-09-07 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–09–07
24 papers selected by
Grigor Varuzhanyan, UCLA

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer.
Extracellular Domain Shedding of TROP2 Activates EGFR Signaling to Drive Prostate Cancer Metastasis.
Proteogenomic Biomarker Profiling for Predicting Radiolabeled Immunotherapy Response in Resistant Prostate Cancer.
Localized high-risk prostate cancer harbors an androgen receptor activity-low subpopulation susceptible to HER2 inhibition.
Salinity-induced capsaicin biosynthesis in Capsicum annuum L.: mechanistic and molecular insights into its potential role in prostate adenocarcinoma.
Interconnected study of molecular pathways: miR-137 as a central element at the intersection of lipid metabolism and prostate carcinogenesis.
ECD, a novel androgen receptor target promotes prostate cancer tumorigenesis by regulating glycolysis.
tRF-21LeuTAA Promotes Oxidative Stress by Altering Glutathione Metabolic Enzymes to Support Prostate Cancer Progression.
Silencing CALB1 enhances prostate cancer radiosensitivity via calcium-mediated mitochondrial dysfunction and cellular senescence.
Cepharanthine hydrochloride inhibits prostate cancer progression by modulating gut microbiota and metabolites.
LHX2 Rewires the Metabolic and Epigenetic Landscape to Drive Tumor Progression in Prostate Cancer.
The effect of neonicotinoid insecticides and triazole fungicides on prostate cancer progression via CYP enzymes, miRNAs, and TF-mediated disruption of steroidogenesis: An integrated in silico approach.
Exploring the anticancer potential of R. tridentata extracts: a cytotoxicity study against human prostate cancer cell lines (LNCaP and DU145).
The role of LKB1 in prostate cancer: implications for tumor progression and therapy.
Untargeted Multiomics of LNCaP Cell Line Treated with a Novel DNA Minor Groove Binder and/or Doxorubicin Using Mass Spectrometry.
EGFL7 Inhibits the Immune Response in Metastatic Castration-Resistant Prostate Cancer by Deactivating Endothelial Intercellular Adhesion Molecule-1.
Chinese medicines as therapeutic options for treating prostate cancer: Therapeutic effects and underlying mechanisms.
An MRI-pathology foundation model for noninvasive diagnosis and grading of prostate cancer.
Research landscape of hydroxamic acid hybrids with therapeutic potential against prostate cancer: a decade of advances.
SNX7 mediates inhibition of autophagy in prostate cancer via activation of CFLIP expression.
TMB-High, MSI-High Castration-Resistant Prostate Cancer Treated With Pembrolizumab.
Relationship Between Prostate Cancer and Benign Hyperplasia: Role of Inflammation-Induced Oxidative Stress, Vitamin C, and Epigenetics.
Bacteriological Identification, Characterization and Changes of Feces Microbiome in Prostate Cancer Patients Undergoing Radiotherapy.
Oligometastatic prostate cancer: new horizons for local treatment with the androgen receptor target therapy.

Res Sq. 2025 Aug 21. pii: rs.3.rs-7360528. [Epub ahead of print]

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer.

Leigh Ellis, Beatriz German, Katherine Morel, Teia Noel, Nadia Boufaied, Deborah Burkhart, Sujun Chen, Felipe Dezem, Xintao Qiu, Henry Long, Stefan DiFazio, Sylvan Baca, Ayesha Shafi, Matthew Freedman, Himisha Beltran, Christopher Sweeney, Housheng He, Myles Brown, Jasmine Plummer, Simon Knott, David Labbé.

Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration or enzalutamide. Together, these data indicate phenotypic plasticity dependence on coordination between EZH2, TTP and mTORC1 signaling that represent novel therapeutic dependencies for this lethal PCa phenotype.

DOI: https://doi.org/10.21203/rs.3.rs-7360528/v1
Cancer Res. 2025 Sep 05.

Extracellular Domain Shedding of TROP2 Activates EGFR Signaling to Drive Prostate Cancer Metastasis.

Shiqin Liu, En-Chi Hsu, Merve Aslan, Fernando Garcia-Marques, Michelle Shen, Alifiani B Hartono, Francisco Solano, Kewei Le, Hyeonji Hwang, Chung S Lee, Abel Bermudez, Rosalie Nolley, Donna M Peehl, James D Brooks, Michael A Liss, Sharon J Pitteri, Tanya Stoyanova.

Metastasis is the main cause of prostate cancer-associated deaths, highlighting the urgent need to determine the mechanisms underlying prostate cancer progression. TROP2 (also known as TACSTD2) is an oncogenic transmembrane surface protein that is highly expressed in metastatic prostate cancer. Naturally occurring cleavage of TROP2 leads to a release of the TROP2 extracellular domain (TECD) into the extracellular environment. In this study, we identified an important functional role of TECD in prostate cancer metastasis. TECD was detectable in media from prostate cancer cells and serum from patients with clinically significant prostate cancer. While shed TECD did not affect prostate cancer cell proliferation and tumor growth, it increased cell migration and invasion in vitro and promoted metastatic colonization and spontaneous metastasis in vivo. TECD interactome and proteomic studies revealed that TECD binds to EGFR and that shed TECD modulates a set of proteins associated with invasion, migration, mTOR signaling, and epithelial-to-mesenchymal transition. Furthermore, elevated shed TECD increased EGFR phosphorylation, resulting in activation of the EGFR-PI3K-AKT-mTOR pathway in prostate cancer. EGFR inhibitors suppressed the invasive ability of prostate cancer cells driven by TECD overexpression, further supporting the key role of EGFR in TECD-mediated prostate cancer progression. This study uncovers a function of TECD in driving prostate cancer progression and provides mechanistic insights into TECD signaling through EGFR.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4855
Cancer Biother Radiopharm. 2025 Aug 29.

Proteogenomic Biomarker Profiling for Predicting Radiolabeled Immunotherapy Response in Resistant Prostate Cancer.

Benchun Yan, Yuqiu Gao, Yulong Zou, Long Zhao, Zhiping Li.

  Treatment resistance prevents patients with preoperative chemoradiotherapy or targeted radiolabeled immunotherapy from achieving a good result, which remains a major challenge in the prostate cancer (PCa) area. A novel integrative framework combining a machine learning workflow with proteogenomic profiling was used to identify predictive ultrasound biomarkers and classify patient response to radiolabeled immunotherapy in high-risk PCa patients who are treatment resistant. The deep stacked autoencoder (DSAE) model, combined with Extreme Gradient Boosting, was designed for feature refinement and classification. The Cancer Genome Atlas and an independent radiotherapy-treated cohort have been utilized to collect multiomics data through their respective applications. In addition to genetic mutations (whole-exome sequencing), these data contained proteomic (mass spectrometry) and transcriptomic (RNA sequencing) data. Maintaining biological variety across omics layers while reducing the dimensionality of the data requires the use of the DSAE architecture. Resistance phenotypes show a notable relationship with proteogenomic profiles, including DNA repair pathways (Breast Cancer gene 2 [BRCA2], ataxia-telangiectasia mutated [ATM]), androgen receptor (AR) signaling regulators, and metabolic enzymes (ATP citrate lyase [ACLY], isocitrate dehydrogenase 1 [IDH1]). A specific panel of ultrasound biomarkers has been confirmed in a state deemed preclinical using patient-derived xenografts. To support clinical translation, real-time phenotypic features from ultrasound imaging (e.g., perfusion, stiffness) were also considered, providing complementary insights into the tumor microenvironment and treatment responsiveness. This approach provides an integrated platform that offers a clinically actionable foundation for the development of radiolabeled immunotherapy drugs before surgical operations.

Keywords:  XGBoost; biomarker profiling; deep stacked autoencoder (DSAE); prostate cancer; radiolabeled immunotherapy; ultrasound biomarkers

DOI:  https://doi.org/10.1177/10849785251366066
J Clin Invest. 2025 Sep 04. pii: e189900. [Epub ahead of print]

Localized high-risk prostate cancer harbors an androgen receptor activity-low subpopulation susceptible to HER2 inhibition.

Scott Wilkinson, Anson T Ku, Rosina T Lis, Isaiah M King, Daniel Low, Shana Y Trostel, John R Bright, Nicholas T Terrigino, Anna Baj, Emily R Summerbell, Kayla E Heyward, Sumeyra Kartal, John M Fenimore, Chennan Li, Cassandra Singler, BaoHan Vo, Caroline S Jansen, Huihui Ye, Nichelle C Whitlock, Stephanie A Harmon, Nicole V Carrabba, Rayann Atway, Ross Lake, David Y Takeda, Haydn T Kissick, Peter A Pinto, Peter L Choyke, Baris Turkbey, William L Dahut, Fatima Karzai, Adam G Sowalsky.

   BACKGROUND: Localized high-risk prostate cancer (PCa) often recurs despite neoadjuvant androgen deprivation therapy (ADT). We sought to identify baseline molecular programs that predict pathologic response and reveal targetable vulnerabilities.
METHODS: We profiled 147 biopsy foci from 48 MRI-visible lesions in 37 patients before 6 months of ADT plus enzalutamide and radical prostatectomy. Residual cancer burden (RCB) at prostatectomy was the primary outcome. Analyses incorporated PTEN loss, TMPRSS2:ERG status, and HER2/androgen receptor (AR) immunohistochemistry on baseline and posttreatment tissues. Findings were evaluated in an external transcriptional cohort (n = 121) and by multiplex immunostaining in an independent cohort (n = 61). Functional assays tested enzalutamide-responsive enhancers near ERBB2 and sensitivity to HER2 inhibition.
RESULTS: A baseline HER2-associated transcriptional program correlated with higher RCB and inversely with AR activity, independent of PTEN and ERG. Exceptional responders had lower HER2 protein in pretreatment biopsies. The inverse AR-HER2 relationship recurred across datasets and multiplex immunostaining, which revealed coexisting AR-high/HER2-low and HER2-high/AR-low subpopulations. Enzalutamide inhibited AR-mediated repression of ERBB2. HER2-high, AR-low cells present before therapy resisted ADT yet were sensitive to HER2 inhibitors; combining HER2 inhibitors with enzalutamide increased tumor cell killing. These findings were reproduced in the external cohort and orthogonal assays.
CONCLUSION: Baseline HER2 activity marks intrinsic resistance to neoadjuvant ADT in localized high-risk PCa and identifies a preexisting, targetable AR-low subpopulation. HER2-directed therapy, alone or with AR blockade, warrants clinical evaluation.
TRIAL REGISTRATION:
CLINICALTRIALS: gov registration: NCT02430480.
FUNDING: Prostate Cancer Foundation; Department of Defense Prostate Cancer Research Program; National Institutes of Health.

Keywords:  Genetics; Molecular pathology; Oncogenes; Oncology; Prostate cancer

DOI:  https://doi.org/10.1172/JCI189900
In Silico Pharmacol. 2025 ;13(3): 122

Salinity-induced capsaicin biosynthesis in Capsicum annuum L.: mechanistic and molecular insights into its potential role in prostate adenocarcinoma.

Amantika Singh, Krishna Kumar Choudhary.

  Prostate cancer incidence is expected to double by 2040, with related deaths rising by 80% highlighting the urgent need for effective prevention and treatment strategies. This growing concern has increased interest in utilising natural plant compounds for cancer therapies. Capsaicin, a key component of Capsicum annuum L., is well renowned for its anti-cancerous properties. Results of quantitative UHPLC-HRMS analysis revealed that capsaicin accumulation was significantly increased in fruits of Capsicum annum L. treated with 50 and 100 mM salinity compared to control (0 mM). These findings suggest that salinity stress enhanced anti-cancer potential of Capsicum annuum L. while presenting a sustainable solution for utilizing salinity-affected lands to enhance capsaicin production. To elucidate capsaicin mechanism against prostate adenocarcinoma, five hub targets were identified through network pharmacology and protein-protein interaction network analysis. KEGG pathway analysis revealed four key targets (ERBB2, HSP90AA1, MTOR, and PIK3CA) involved in tumour growth, cell proliferation, and survival via the PI3K-Akt, MAPK, and androgen receptor pathways. Gene (GEPIA2) and protein expression analysis (Human Protein Atlas) confirmed their overexpression in prostate adenocarcinoma cells, underscoring their therapeutic relevance. Docking studies along with molecular dynamic simulations further demonstrated significant binding affinities between capsaicin and these targets (ERBB2: - 6.207; HSP90AA1: - 4.846; MTOR: - 6.451 and PIK3CA: - 6.720 Kcal/mol) suggest that capsaicin may disrupt the PI3K/Akt/mTOR and MAPK signaling pathways, potentially leading to the suppression of prostate cancer. Our Insilco based findings suggest that capsaicin interacts with key molecular targets associated with prostate cancer pathways, further in vivo validations are necessary to confirm its therapeutic potential.

Keywords:  Anti-cancerous; Capsaicin; Molecular targets; Prostate adenocarcinoma; Salinity stress; UHPLC-HRMS

DOI:  https://doi.org/10.1007/s40203-025-00416-3
Einstein (Sao Paulo). 2025 ;pii: S1679-45082025000100249. [Epub ahead of print]23 eAO1601

Interconnected study of molecular pathways: miR-137 as a central element at the intersection of lipid metabolism and prostate carcinogenesis.

Karina Serafim da Silva, Vanessa Ribeiro Guimarães, Feres Camargo Maluf, Gabriel Arantes Dos Santos, Juliana Alves de Camargo, Iran Amorim da Silva, Katia Ramos Moreira Leite, Sabrina Thalita Dos Reis, Nayara Izabel Viana, Miguel Srougi, Ruan Pimenta.

OBJECTIVE: To evaluate the roles of miR-137 and its target genes in lipid metabolism and prostate tumorigenesis.
METHODS: We used a series of bioinformatic approaches to establish the relationship between miR-137 and its target genes. We mapped the metabolic pathways of interest in the Reactome database and identified the central target genes of miR-137 in this pathway using four platforms: Reactome, miRDB, miRmap, and TargetScan. To assess the expression and association with clinical parameters, we obtained information from the UALCAN, OncoDB, and GEPIA2 databases using a dataset of patients with prostate cancer from The Cancer Genome Atlas. For functional enrichment analysis and construction of the protein-protein interaction network, we used the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and STRING.
RESULTS: Our in silico study of The Cancer Genome Atlas database revealed that miR-137 is underexpressed in tumor tissues, and its reduction is associated with poor prognosis. An intriguing set of eight genes within the PPARα pathway: PPARGC1A, PPARGC1B, NCOA1, NCOA2, NCOA3, MED1, MED27, and ESRRA displayed synergy, positive correlations, and synchronized expression patterns in adipose, hepatic, and prostatic tissues, all linked to the enigmatic processes of metabolic regulation. Among the highlighted genes, ESRRA was overexpressed in the malignant environment, whereas its counterparts remained underexpressed. The plot was thickened with associations between the expression of NCOA1, NCOA3, and MED27, lymph node involvement, and the overexpression of several genes linked to advanced prostate cancer stages. An intriguing pattern emerged, with patients exhibiting reduced disease-free survival overexpressing NCOA2, NCOA3, MED27, and ESRRA.
CONCLUSION: This study elucidates the possibility that miR-137 subtly modulates metabolic genes in prostate cancer, suggesting its latent therapeutic potential as a biomarker for disease progression.
BACKGROUND: ■ The reduction of miR-137 in tumor tissues is associated with a worse prognosis.
BACKGROUND: ■ miR-137 has eight oncogenically relevant target genes acting in the PPARα lipid pathway.
BACKGROUND: ■ NCOA1, NCOA3, MED27, and ESRRA are associated with advanced prostate cancer.
BACKGROUND: ■ miR-137 exhibits significant clinical potential by repressing the activation of pathways that influence prostate tumorigenesis in hyperstimulated metabolic environments.
BACKGROUND: Prostate cancer progression is sustained by the simultaneous activation of pathways involving lipid uptake and de novo synthesis. In this context, miR-137 inhibits adipogenic differentiation and may reduce lipid uptake by tumor cells by modulating the PPAR/ p160/ESRRA axis, considerably attenuating metabolic effects and suppressing prostate tumorigenesis.

DOI: https://doi.org/10.31744/einstein_journal/2025AO1601
Oncogene. 2025 Sep 04.

ECD, a novel androgen receptor target promotes prostate cancer tumorigenesis by regulating glycolysis.

Mohsin Raza, Asher Rajkumar Rajan, Benjamin B Kennedy, Timothy E Reznicek, Farshid Oruji, Sameer Mirza, M Jordan Rowley, Carsten Stephan, Glen Kristiansen, Kaustubh Datta, Bhopal C Mohapatra, Hamid Band, Vimla Band.

Androgen receptor (AR)-mediated signaling is essential for PC tumorigenesis. In the TCGA database we observed a positive correlation between ECD and AR expression. Consistently, Dihydrotestosterone (DHT) treatment of PC cell lines increased ECD mRNA and protein levels, and AR knockdown (KD) reduced ECD expression. Bioinformatic analysis predicted three consensus androgen response elements in the ECD promoter, and DHT treatment increased AR occupancy at the ECD promoter, and enhanced ECD promoter activity. Enzalutamide treatment decreased ECD levels, and ECD knockout (KO) in PC cells reduced oncogenic traits, suggesting a functional role of ECD to maintain PC oncogenesis. ECD mRNA and protein are overexpressed in PC patient tissues, and its overexpression predicts shorter survival. Overexpression of ECD in PC cell lines enhanced the oncogenic traits in vitro and developed faster and larger highly proliferative xenograft tumors. RNA-seq analysis of mouse tumors revealed an increase in mRNA levels of several glycolytic genes. ECD associates with mRNA of key glycolytic genes and is required for their stability, consistent with our recent demonstration of ECD is an RNA binding protein. Higher glucose uptake and glycolysis was seen upon ECD overexpression in PC cells. Together, we demonstrate the role of a novel AR target gene ECD in PC tumorigenesis.

DOI: https://doi.org/10.1038/s41388-025-03559-x
Cancer Res. 2025 Aug 29.

tRF-21LeuTAA Promotes Oxidative Stress by Altering Glutathione Metabolic Enzymes to Support Prostate Cancer Progression.

Xiaoyu Guo, Jinjing Zhong, Jingyu Qian, Xiuyi Pan, Xinyue Zhang, Xueqin Chen, Hao Zeng, Ni Chen, Ling Nie, Ting Yu, Qiao Zhou.

Transfer RNA (tRNA)-derived fragments (tRFs) are a class of small non-coding RNAs that have recently been implicated in various physiological and pathological processes, including tumor development and progression. Identification of the roles of tRFs in cancer could provide insights into tumor biology and treatment strategies. Here, we found that tRF-21LeuTAA supported progression of prostate cancer by regulating glutathione metabolic enzymes and promoting reactive oxygen species (ROS) accumulation. Nuclear tRF-21LeuTAA upregulated leucyl aminopeptidase 3 (LAP3) by binding to its promoter and recruiting H3K27ac acetyltransferase P300 and transcription factor STAT1. The increased cystine-glycine dipeptidase activity of LAP3 led to increased degradation of the antioxidant glutathione. Alternatively, cytoplasmic tRF-21LeuTAA suppressed glutathione-S-transferase mu 3 (GSTM3) by repressing its mRNA post-transcriptionally, which further elevated ROS by decreasing scavenger glutathione S-transferase activity. The accumulation of intracellular ROS downstream of tRF-21LeuTAA-mediated alterations in LAP3 and GSTM3 resulted in AKT activation. Overexpression of tRF-21 promoted proliferation and migration of prostate cancer cells, formation of spheroids, and initiation and growth of tumors in a xenograft model. In patients, elevated tRF-21 and LAP3 levels were associated with unfavorable survival outcomes. The regulatory circuitry revealed in the present study may represent potential therapeutic targets for prostate cancer as well as various malignancies with tRF-21 overexpression.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0273
Cell Calcium. 2025 Aug 26. pii: S0143-4160(25)00080-6. [Epub ahead of print]132 103071

Silencing CALB1 enhances prostate cancer radiosensitivity via calcium-mediated mitochondrial dysfunction and cellular senescence.

Chen Gong, Senmao Li, Ye An, Chadanfeng Yang, Zhiyong Tan, Wujie Chen, Dihao Lv, Haichao Wu, Haifeng Wang, Shi Fu, Haihao Li, Yanjie Kong, Yinglong Huang, Mingxia Ding.

   BACKGROUND: Prostate cancer remains a leading cause of cancer-related deaths in men, with radioresistance limiting treatment efficacy. This study investigates the role of Calbindin 1 (CALB1), a calcium-binding protein regulated by miR-186-5p, in prostate cancer progression and radiation response.
METHODS: CALB1 expression was analyzed using GEO and TCGA datasets, and the regulatory relationship with miR-186-5p was validated. Functional studies including CALB1 knockdown, calcium chelation, and mitochondrial rescue interventions were conducted in prostate cancer cells, spheroids, and xenograft models, assessing proliferation, senescence, calcium homeostasis, and radiation response.
RESULTS: We identified CALB1 as a target of downregulated miR-186-5p in prostate cancer. CALB1 silencing inhibited prostate cancer growth by inducing cellular senescence through calcium dysregulation, mitochondrial dysfunction, and oxidative stress. CALB1 depletion significantly enhanced radiosensitivity both in vitro and in vivo, with calcium chelation or mitochondrial interventions partially rescuing these effects.
CONCLUSIONS: CALB1 regulates prostate cancer progression and radiation response by maintaining calcium homeostasis. Its depletion triggers calcium overload and mitochondrial dysfunction, enhancing radiation sensitivity and identifying CALB1 as a potential therapeutic target.

Keywords:  CALB1; Calcium homeostasis; Cellular senescence; Prostate cancer; Radiosensitivity; miR-186-5p

DOI:  https://doi.org/10.1016/j.ceca.2025.103071
Front Pharmacol. 2025 ;16 1627656

Cepharanthine hydrochloride inhibits prostate cancer progression by modulating gut microbiota and metabolites.

Hui Li, Xing Luo, Peng He, Zongming Dong, Yongming Jia, Bishao Sun, Ji Zheng, Jingzhen Zhu.

   Background: Cepharanthine Hydrochloride (CH) is widely used in clinical settings to alleviate leukopenia caused by various tumors following radiotherapy and chemotherapy. However, it remains unclear whether CH have an inhibitory effect on the progression of prostate cancer, and whether this effect is mediated by gut microbiota. To address this question, the present study constructed normal mouse models of prostate cancer, as well as antibiotic-treated mouse models of prostate cancer.
Methods: CH were then administered via gavage to both groups of model mice. After treatment, the tumor sizes of the mice were measured, and feces, blood, and tumor tissues from both groups were collected for 16S rDNA, metabolomics, and transcriptomics sequencing analysis.
Results: Results showed CH treatment significantly suppressed prostate cancer growth in mice without antibiotic cocktail pretreatment, but not in antibiotic-pretreated mice. 16S rRNA sequencing revealed distinct gut microbiota alterations in CH-Ctrl versus Ctrl/CH-ABX groups, with increased g_Blautia, g_Lactobacillus, g_Butyricicoccus and decreased g_Akkermansia abundances. Metabolomic analysis identified 240 and 123 differentially abundant metabolites in CH-Ctrl vs Ctrl and CH-ABX, respectively. RNA-seq detected 579 and 530 differentially expressed genes in CH-Ctrl vs Ctrl and CH-ABX, respectively. Correlation analysis of differential gut microbiota, metabolites, and genes suggested that CH might inhibit prostate cancer growth by increasing the relative abundance of g_Blautia, g_Lactobacillus, and g_Butyricicoccus, suppressing g_Akkermansia proliferation, enhancing Acetylglycine metabolite production, upregulating Ttpa, Gm14964, Shc3, Elovl4 gene expression, and downregulating Gm10531, Bc021767 gene expression.
Conclusion: This study is the first to explore the potential mechanisms of gut microbiota-mediated CH treatment for prostate cancer, providing a scientific basis for the application of CH in PCa therapy.

Keywords:  antibiotic cocktail; cepharanthine hydrochloride; gut microbiota; metabolites of gut microbiota; prostate cancer

DOI:  https://doi.org/10.3389/fphar.2025.1627656
Cancer Res. 2025 Sep 03.

LHX2 Rewires the Metabolic and Epigenetic Landscape to Drive Tumor Progression in Prostate Cancer.

Jun Jiang, Shaojie Liu, Chao Xu, Limin He, Hongji Li, Yike Zhou, Zhengxuan Li, Yu Li, Fa Yang, Yuchen Wei, Tong Lu, Keying Zhang, Jingliang Zhang, Pang Wang, Li Guo, Changhong Shi, Weihong Wen, Rui Zhang, Donghui Han, Weijun Qin.

Neuroendocrine prostate cancer (NEPC) evolves as an aggressive phenotype during prolonged androgen deprivation therapy, lacking effective clinical management. Here, we elucidated a reciprocal metabolic-epigenetic mechanism involving a positive feedback loop between glycolysis and the transcription factor LHX2 that promotes PCa progression. Mechanistically, enzalutamide-mediated inhibition of the androgen receptor (AR) led to upregulation of key glycolytic enzymes. Elevated glycolysis resulted in lactate accumulation and subsequent histone lactylation, which in turn enhanced LHX2 expression. Reciprocally, LHX2 transcriptionally activated the lactate dehydrogenase LDHA, which further amplified lactate production. Furthermore, LHX2 augmented the expression of the lineage-determining enzyme DNMT1, potentiating neuroendocrine gene expression and tumor growth. Significantly, the antiviral agent paritaprevir could directly bind to LHX2, effectively suppressing neuroendocrine marker expression and tumor progression. These findings uncover a potential role for LHX2 in orchestrating NEPC development, offering putative therapeutic targets for treating this aggressive cancer phenotype and overcoming drug resistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0587
Toxicol Ind Health. 2025 Sep 04. 7482337251371763

The effect of neonicotinoid insecticides and triazole fungicides on prostate cancer progression via CYP enzymes, miRNAs, and TF-mediated disruption of steroidogenesis: An integrated in silico approach.

Mine Caglayan.

  Neonicotinoid insecticides and triazole fungicides are widely used in agriculture, often in combination with other pesticides, leading to concerns about potential health effects. This study investigated the combined effect of these chemicals using the Comparative Toxicogenomics Database (CTD) to identify common target genes, followed by functional enrichment analysis and gene-gene and protein-protein interaction assessments. In this study, it was determined that pesticides may interfere with biological processes such as steroid hydroxylase activity, oxidoreductase activity, and steroid metabolism, and cause hormonal imbalances and endocrine system disorders. In addition, among the 10 genes identified, CYP3A5 and CYP3A7 gene expression differed significantly between prostate cancer and normal prostate tissues, and this was supported by UALCAN data. In addition, previous studies have confirmed that hsa-miR-27b, one of the prominent miRNAs in this study, and transcription factors (PROX1 and ESR2) are associated with prostate cancer. Similar to our study, previous studies have confirmed that triazole fungicides disrupt testosterone homeostasis and steroidogenesis, while neonicotinoids damage the prostate due to their effects on androgen receptors. These genes, miRNAs, and transcription factors appear to mediate the effects of these pesticides on cancer pathways and suggest a link to prostate cancer. In conclusion, this study demonstrated that concurrent exposure to neonicotinoid insecticides and triazole fungicides may damage the prostate and potentially contribute to the development of prostate neoplasia. These findings emphasise the importance of further in vitro and in vivo validation to establish a definitive causal relationship and provide insight into the toxicological effects of pesticide exposure on prostate health.

Keywords:  in silico toxicity; neonicotinoid insecticides; prostate cancer; toxicogenomic; triazole fungicides

DOI:  https://doi.org/10.1177/07482337251371763
Med Oncol. 2025 Sep 05. 42(10): 463

Exploring the anticancer potential of R. tridentata extracts: a cytotoxicity study against human prostate cancer cell lines (LNCaP and DU145).

Ali Kudamba, Godfrey S Bbosa, Allan Lugaajju, Henry Wabinga, Nixon Niyonzima, Moses Ocan, Ali M Damani, Hussein M Kafeero, Jamilu E Ssenku, Shaban A Okurut, Muniiru Lubowa, Abdul Walusansa, S Sivagami Sivasundaram, Shobana Shampath, Haruna Muwonge.

  This study investigates the cytotoxic effects of R. tridentata extracts on prostate cancer cells, providing insight into its potential therapeutic benefits and scientific validation for its traditional use in cancer treatment. The cytotoxicity of R. tridentata extracts was evaluated on prostate cancer cell lines (LNCaP and DU 145) using the MTT assay, with doxorubicin as a reference standard. Our findings demonstrated significant concentration- and time-dependent cytotoxic effects of the extracts on both cell lines (p < 0.0024 to p < 0.0002). Notably, the methanol extract exhibited potent cytotoxicity, with IC50 values ranging from 124.07 to 211 μg/mL (DU145) and 100 to 180 μg/ml (LNCaP) over 24-72 h (p < 0.0024 to p < 0.0001), highlighting its therapeutic potential. This study unveils the promising cytotoxic activity of R. tridentata extracts, particularly methanol extracts, against prostate cancer cells, showcasing their concentration- and time-dependent effects. These findings underscore the potential of plant-derived extracts as therapeutic agents for cancer treatment, warranting further research.

Keywords:   R. tridentata ; Cytotoxic; DU145; LNCAP; Plant extracts; Prostate carcinoma cell lines

DOI:  https://doi.org/10.1007/s12032-025-02953-5
Front Cell Dev Biol. 2025 ;13 1629844

The role of LKB1 in prostate cancer: implications for tumor progression and therapy.

Yuwei Liang, Hongliang Cao, Zhijun Tang, Shuxin Li, Gang Yang, Shuai Dong, Hao Du, Jinguo Wang.

  Liver kinase B1 (LKB1/STK11) is a key tumor suppressor that regulates cellular metabolism, epigenetic states, and multiple signaling pathways in prostate cancer (PCa). Recent studies reveal that both genetic and non-genetic LKB1 loss drives metabolic reprogramming, lineage plasticity, and treatment resistance, mainly through dysregulation of the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), and Hedgehog (Hh) pathways. This review summarizes current evidence on LKB1-centered networks in PCa, highlighting the potential link between LKB1 inactivation, epigenetic remodeling, and aggressive tumor phenotypes. Special attention is given to recent studies on the impact of combined LKB1 and Phosphatase and Tensin Homolog (PTEN) loss on tumor differentiation. Finally, we discuss emerging therapeutic strategies aimed at the metabolic and epigenetic features of LKB1-deficient PCa, with a focus on the prospects for biomarker-driven precision medicine to address resistance and improve patient outcomes.

Keywords:  LKB1; epigenetic regulation; precision therapeutic targets; prostate cancer; signaling pathway regulation

DOI:  https://doi.org/10.3389/fcell.2025.1629844
J Proteome Res. 2025 Sep 04.

Untargeted Multiomics of LNCaP Cell Line Treated with a Novel DNA Minor Groove Binder and/or Doxorubicin Using Mass Spectrometry.

Ruba A Zenati, Nelson C Soares, Hasan Y Alniss, Hamza M Al-Hroub, Raafat El-Awady, Ahmad Y Abuhelwa, Wafaa S Ramadan, Shereen M Aleidi, Waseem El-Huneidi, Eman Abu-Gharbieh, Karem H Alzoubi, Yasser Bustanji, Mohammad H Semreen.

  Prostate cancer (PCa) remains a major global health concern, ranking among the most prevalent cancer in men worldwide. Despite the availability of various therapeutic options, the clinical efficacy of current anti-PCa agents is often compromised by drug resistance and adverse effects. DNA minor groove binders offer a potential therapeutic alternative, owing to their selective mechanism of action and favorable safety profiles. In the present study, we utilized a multiomics strategy to investigate the molecular impact of novel compound MGB4. LNCaP cells were treated with doxorubicin, MGB4, or a combination of both, followed by LC-MS/MS-based untargeted proteomics and metabolomics analyses. One-way ANOVA (p-value <0.05) revealed 55 significantly dysregulated proteins and 57 altered metabolites across treatments. Our findings indicate that both MGB4 and doxorubicin impacted key cellular pathways, including inhibition of translation and alterations in sphingolipid and amino acid metabolism, while doxorubicin and the combination therapy also reduced spermine and spermidine metabolism. Notably, the combined treatment exhibited synergistic effects, significantly impacting purine metabolism and reducing metabolite levels more than individual therapies. This study provides key molecular insights into MGB4 and doxorubicin's mechanisms, supporting MGB4 as a potential prostate cancer drug candidate.

Keywords:  LC-MS/MS-QTOF; doxorubicin; metabolomics; minor groove binders (MGBs); prostate cancer; proteomics

DOI:  https://doi.org/10.1021/acs.jproteome.5c00135
World J Mens Health. 2025 Aug 11.

EGFL7 Inhibits the Immune Response in Metastatic Castration-Resistant Prostate Cancer by Deactivating Endothelial Intercellular Adhesion Molecule-1.

Seung Soo Lee, Ji Young Lee, Hyun Jung Lee, Sung-Woo Park.

   PURPOSE: Epidermal growth factor-like 7 (EGFL7) has been implicated in various cancers, but its role in different stages of prostate cancer (PCa), particularly metastatic castration-resistant prostate cancer (mCRPC), remains unclear. This study aimed to investigate the biological function of EGFL7 and its association with immune regulation in PCa.
MATERIALS AND METHODS: We quantified EGFL7 and intercellular adhesion molecule-1 (ICAM-1) levels in serum and prostate tissue specimens from patients with benign prostatic hyperplasia (BPH), localized PCa, and mCRPC. To explore its functional role, EGFL7 expression was either silenced or overexpressed in DU145 and PC3 cells using siRNA or pCMV-GFP, respectively. Xenograft experiments were conducted in nude mice using transfected DU145/PC3 cells, followed by post-hoc microarray analysis of tumor tissues.
RESULTS: Our findings revealed that EGFL7 expression was significantly higher in both serum and tumor tissues of mCRPC patients compared to those with BPH or localized PCa. ICAM-1 levels were inversely correlated with EGFL7 expression. Knockdown of EGFL7 in DU145 cells suppressed cell proliferation, migration, and invasion, while in vivo studies demonstrated that EGFL7 silencing inhibited tumor growth and increased ICAM-1 expression along with CD4/8 lymphocyte infiltration. Conversely, overexpression of EGFL7 in PC3 cells promoted tumor progression and reduced ICAM-1 levels.
CONCLUSIONS: These findings suggest that EGFL7 overexpression in mCRPC suppresses immune cell infiltration by downregulating endothelial ICAM-1. Our study highlights the potential of EGFL7 as a therapeutic target in advanced PCa.

Keywords:  Cell adhesion molecules; Endothelium; Epidermal growth factor; Immune evasion; Prostatic neoplasms

DOI:  https://doi.org/10.5534/wjmh.250111
J Ethnopharmacol. 2025 Aug 27. pii: S0378-8741(25)01163-8. [Epub ahead of print]354 120471

Chinese medicines as therapeutic options for treating prostate cancer: Therapeutic effects and underlying mechanisms.

Shenglong Li, Shuaishuai Jing, Jiuyun Zhou, Hui Li, Pengdong Yin, Qingwei Zhang, Meisheng Gong, Yongqiang Zhao, Ganggang Lu, Guangwei Jin, Xixiang Li, Yonglin Liang, Lining Su.

   ETHNOPHARMACOLOGICAL RELEVANCE: Prostate Cancer (PCa) remains a leading malignancy in males, with significant morbidity and mortality. Despite advancements in treatment, challenges like resistance, recurrence, and metastasis persist. Traditional Chinese Medicine (TCM) offers a promising adjunctive approach, enhancing treatment efficacy, reducing toxicity, delaying progression, and improving quality of life.
AIM OF THE STUDY: This study reviews PCa pathogenesis and evaluates the therapeutic potential of TCM through clinical efficacy data and mechanistic investigations. We further outline TCM's capacity to modulate PCa cellular dynamics through multi-scale biological interactions, establishing a framework for its application in PCa management. Our findings offer insights into TCM-based strategies for overcoming therapeutic limitations in prostate oncology.
MATERIALS AND METHODS: This paper provides a systematic summary of PCa pathogenesis and analyzes the clinical efficacy and molecular mechanisms of TCM in treating PCa. Findings are based on searches using keywords such as 'prostate cancer,' 'pathogenesis,' 'Chinese herbal medicine,' 'herbal medicine,' 'traditional Chinese medicine,' and 'active components of Chinese medicine' in PubMed, Web of Science, EMBASE, Cochrane Library, Wanfang Database, and China National Knowledge Infrastructure (CNKI).
INCLUSION CRITERIA: ① Original clinical studies, observational studies, RCTs, and meta-analyses related to the topic. ② Articles published in the last 10 years on PCa treatment and mechanisms in TCM. ③ Studies investigating the mechanisms, treatment strategies, or efficacy of Chinese medicine in PCa. ④ Research on the molecular mechanisms, therapeutic effects, or potential of Chinese herbs or components for PCa.
EXCLUSION CRITERIA: ① Abstracts, conference proceedings, opinion pieces, or non-peer-reviewed articles. ② Studies with low methodological quality (e.g., lacking control groups or detailed drug dosages). ③ Irrelevant studies or those focusing on unrelated diseases.
RESULTS: PCa pathogenesis involves gene mutations, androgen signaling abnormalities, epigenetic changes, inflammation, and metabolic reprogramming. TCM modulates the internal environment to delay progression, extend survival, improve quality of life, enhance immune defense, and alleviate chemotherapy and radiation side effects. TCM also inhibits tumor cell proliferation, metastasis, promotes apoptosis, regulates autophagy and ferroptosis, and reverses chemotherapy resistance, exerting anti-PCa effects through these pathways.
CONCLUSIONS: PCa pathogenesis involves genetics, hormones, inflammation, and metabolism, and remains incompletely understood. TCM significantly inhibits PCa progression by regulating cell behavior, improving symptoms, and reducing adverse effects. However, large-scale, multi-center studies are needed to support its application.

Keywords:  Pathogenesis; Prostate cancer; Therapeutic effects; Traditional Chinese medicine; Underlying mechanisms

DOI:  https://doi.org/10.1016/j.jep.2025.120471
Nat Cancer. 2025 Sep 02.

An MRI-pathology foundation model for noninvasive diagnosis and grading of prostate cancer.

Lizhi Shao, Chao Liang, Ye Yan, Haibin Zhu, Xiaoming Jiang, Meiling Bao, Pan Zang, Xiazi Huang, Hongyu Zhou, Pei Nie, Liang Wang, Jie Li, Shudong Zhang, Shancheng Ren.

Prostate cancer is a leading health concern for men, yet current clinical assessments of tumor aggressiveness rely on invasive procedures that often lead to inconsistencies. There remains a critical need for accurate, noninvasive diagnosis and grading methods. Here we developed a foundation model trained on multiparametric magnetic resonance imaging (MRI) and paired pathology data for noninvasive diagnosis and grading of prostate cancer. Our model, MRI-based Predicted Transformer for Prostate Cancer (MRI-PTPCa), was trained under contrastive learning on nearly 1.3 million image-pathology pairs from over 5,500 patients in discovery, modeling, external and prospective cohorts. During real-world testing, prediction of MRI-PTPCa demonstrated consistency with pathology and superior performance (area under the curve above 0.978; grading accuracy 89.1%) compared with clinical measures and other prediction models. This work introduces a scalable, noninvasive approach to prostate cancer diagnosis and grading, offering a robust tool to support clinical decision-making while reducing reliance on biopsies.

DOI: https://doi.org/10.1038/s43018-025-01041-x
Future Med Chem. 2025 Aug 28. 1-13

Research landscape of hydroxamic acid hybrids with therapeutic potential against prostate cancer: a decade of advances.

Jing Fan, Rui-Hong Wu, He Li, Chao Wang, Ling-Zhi Chen, Lian-Shun Feng.

  Prostate cancer, a malignant tumor arising from the prostate gland, ranks as one of the most commonly diagnosed cancers in men globally and the eighth leading cause of cancer-related mortality worldwide. Hydroxamic acid derivatives, identified as outstanding histone deacetylase (HDAC) inhibitors, are a class of compounds with significant research interest in prostate cancer due to their diverse mechanisms of action, primarily involving epigenetic regulation and targeted enzyme inhibition. Recent studies highlight that incorporating diverse anti-prostate cancer pharmacophores with a hydroxamic acid moiety can potentiate their inhibitory efficacy against HDACs or endow them with multi-target HDAC inhibitory capabilities. Furthermore, hydroxamic acid hybrids possess inherent potential to enhance therapeutic efficacy through multi-target engagement, circumvent drug resistance via epigenetic reprogramming, improve pharmacokinetic profiles through structural optimization, and mitigate off-target toxicity through enhanced receptor selectivity, representing promising scaffolds for designing novel therapeutic candidates against prostate cancer. This review comprehensively outlines the research landscape of hydroxamic acid hybrids with therapeutic potential in prostate cancer, spanning from 2016 to the present, to uncover new avenues for discovering novel therapeutic candidates.

Keywords:  Hydroxamic acid; histone deacetylases; hybrids; mechanisms of action; prostate cancer; structure-activity relationships

DOI:  https://doi.org/10.1080/17568919.2025.2552634
Discov Oncol. 2025 Aug 29. 16(1): 1656

SNX7 mediates inhibition of autophagy in prostate cancer via activation of CFLIP expression.

Liang Qin, Fan Yang, Zhuifeng Guo, Xuwei Lu, Jiawen Wu, Dongzhen Jiang, Ning Yang.



Keywords:   SNX7 ; Autophagy; CFLIP; Prostate cancer

DOI:  https://doi.org/10.1007/s12672-025-03446-7
IJU Case Rep. 2025 Sep;8(5): 449-453

TMB-High, MSI-High Castration-Resistant Prostate Cancer Treated With Pembrolizumab.

Satoshi Muraoka, Hisanobu Tosuji, Yuya Iwahashi, Hiroki Kawabata, Ryusuke Deguchi, Takahito Wakamiya, Shimpei Yamashita, Yasuo Kohjimoto, Isao Hara.

   Introduction: The use of pembrolizumab in patients with microsatellite instability-high (MSI-high) and tumor mutation burden-high (TMB-high) prostate cancer in Japan is not widely reported. Here, we report the case of a patient with MSI-high and TMB-high prostate cancer who responded well to pembrolizumab after multiple systemic treatments.
Case Presentation: A 68-year-old Japanese man was diagnosed with cT4N1M1a prostate cancer. He was treated with several androgen receptor signaling inhibitors and chemotherapy. After intense systemic treatment, disease progression was confirmed, and genomic testing detected MSI-high and TMB-high. However, treatment with pembrolizumab resulted in marked prostate-specific antigen reduction and significant shrinkage of metastases.
Conclusion: Genomic tests should be considered for high-grade tumors. MSI-high and TMB-high prostate cancer responded well to pembrolizumab in this case, but patients should be carefully monitored for the development of side effects after administration of pembrolizumab.

Keywords:  microsatellite instability‐high; pembrolizumab; prostate cancer; tumor mutation burden‐high

DOI:  https://doi.org/10.1002/iju5.70062
World J Mens Health. 2025 Aug 06.

Relationship Between Prostate Cancer and Benign Hyperplasia: Role of Inflammation-Induced Oxidative Stress, Vitamin C, and Epigenetics.

Ewelina Zarakowska, Jolanta Guz, Daniel Gackowski, Ryszard Olinski.

  Benign prostatic hyperplasia and prostate cancer (PC) frequently affect aging men, both involving irregular cell growth in the prostate. Inflammation is a major contributor to these conditions, whereas DNA methylation and hydroxymethylation are specifically involved in PC development. In this review, we address several potential factors influencing the progression of PC, including DNA epigenetic marks, ascorbate (vitamin C) concentration in the blood plasma, and its intracellular levels in leukocytes and prostate tissues. Moreover, a new aspect concerning the involvement of leukocytes (white blood cells) in PC formation will also be discussed, highlighting their potential utility for assessing early PC development through a minimally invasive approach.

Keywords:  Ascorbic acid; Epigenome; Inflammation; Oxidative stress; Prostatic hyperplasia; Prostatic neoplasms

DOI:  https://doi.org/10.5534/wjmh.250116
Cancer Manag Res. 2025 ;17 1825-1841

Bacteriological Identification, Characterization and Changes of Feces Microbiome in Prostate Cancer Patients Undergoing Radiotherapy.

Aleksandra Bogumiła Florkiewicz, Paweł Fijałkowski, Piotr Fijałkowski, Michał Złoch, Agnieszka Ludwiczak, Dorota Gabryś, Wioletta Miśta, Jolanta Mrochem-Kwarciak, Anna Jędrzejewska, Ewa Telka, Małgorzata Rabsztyn, Grażyna Czeszewska-Rosiak, Radik Mametov, Andrzej Tretyn, Paweł Pomastowski.

   Purpose: To investigate the bacteriological characteristics of the gut microbiome in patients with prostate cancer and changes during and after radiation therapy.
Patients and Methods: Forty-one prostate cancer (PCa) patients treated with radiation therapy were included in the study. Fecal samples were collected at three points: before gold marker implantation into the prostate gland (K1), at the start (K2), and last day of radiotherapy (K3). Microbial identification was performed using MALDI-TOF MS, which allowed for precise identification at the species and genus levels. Blood biochemical parameters were assessed, and correlation analyses were performed.
Results: In total, 291 microbial isolates were identified, with the most common genera being Escherichia (N=120), Streptococcus (N=31), and Enterococcus (N=30). A significant decrease in E. coli was observed in K3 compared with K1 and K2, whereas Citrobacter appeared exclusively at K2. Additionally, liver enzyme levels decreased, and IL-6 levels increased during treatment. These findings indicate significant shifts in the gut microbiota due to radiotherapy.
Conclusion: Radiation therapy alters the gut microbiota composition in patients with PCa, reduces microbial diversity, and promotes the growth of opportunistic pathogens. These changes are linked to biochemical parameters, suggesting a potential impact on health. Further research is needed to explore microbiome-targeted interventions during treatment.

Keywords:  fecal; matrix-assisted laser desorption/ionization time-of-flight; microbiome; microorganisms; prostate cancer

DOI:  https://doi.org/10.2147/CMAR.S517416
Chin Clin Oncol. 2025 Aug;14(4): 37

Oligometastatic prostate cancer: new horizons for local treatment with the androgen receptor target therapy.

Giulio Francesco Reale, Riccardo Scarlatti, Diana Aresu.



Keywords:  Prostate cancer; multimodal treatment; oligometastatic; prostate-specific membrane antigen-positron emission tomography (PSMA-PET); radio-guided

DOI:  https://doi.org/10.21037/cco-25-44