bims-meproc 2025-05-04 papers

Issue of 2025–05–04
four papers selected by
Grigor Varuzhanyan, UCLA

Investig Clin Urol. 2025 May;66(3): 227-235

PDK4 expression and tumor aggressiveness in prostate cancer.

Eun Hye Lee, Yun-Sok Ha, Bo Hyun Yoon, Minji Jeon, Dong Jin Park, Jiyeon Kim, Jun-Koo Kang, Jae-Wook Chung, Bum Soo Kim, Seock Hwan Choi, Hyun Tae Kim, Tae-Hwan Kim, Eun Sang Yoo, Tae Gyun Kwon.

PURPOSE: Prostate cancer ranks as the second most common cancer in men globally, representing a significant cause of cancer-related mortality. Metastasis, the spread of cancer cells from the primary site to distant organs, remains a major challenge in managing prostate cancer. Pyruvate dehydrogenase kinase 4 (PDK4) is implicated in the regulation of aerobic glycolysis, emerging as a potential player in various cancers. However, its role in prostate cancer remains unclear. This study aims to analyze PDK4 expression in prostate cancer cells and human samples, and to explore the gene's clinical significance.
MATERIALS AND METHODS: PDK4 expression was detected in cell lines and human tissue samples. Migration ability was analyzed using Matrigel-coated invasion chambers. Human samples were obtained from the Kyungpook National University Chilgok Hospital.
RESULTS: PDK4 expression was elevated in prostate cancer cell lines compared to normal prostate cells, with particularly high levels in DU145 and LnCap cell lines. PDK4 knockdown in these cell lines suppressed their invasion ability, indicating a potential role of PDK4 in prostate cancer metastasis. Furthermore, our results revealed alterations in epithelial-mesenchymal transition markers and downstream signaling molecules following PDK4 suppression, suggesting its involvement in the modulation of invasion-related pathways. Furthermore, PDK4 expression was increased in prostate cancer tissues, especially in castration-resistant prostate cancer, compared to normal prostate tissues, with PSA and PDK4 expression showing a significantly positive correlation.
CONCLUSIONS: PDK4 expression in prostate cancer is associated with tumor invasion and castration status. Further validation is needed to demonstrate its effectiveness as a therapeutic target.

Keywords: Aggression; Biomarkers; Metastasis; Prostate cancer

DOI: https://doi.org/10.4111/icu.20240434

Small. 2025 Apr 26. e2408996

Targeting Melatonin to Mitochondria Mitigates Castration-Resistant Prostate Cancer by Inducing Pyroptosis.

Xiaohui Chen, Mairehaba Kadier, Mengting Shi, Kefeng Li, Hongtao Chen, Yongzhen Xia, Qiaohua Wang, Rongna Li, Yili Long, Jingbo Qin, Hao Wang, Guanmin Jiang.

Prostate cancer frequently progresses to castration-resistant prostate cancer (CRPC) following androgen deprivation therapy, presenting a significant clinical challenge. Targeting tumor metabolism, particularly mitochondrial pathways, offers a promising strategy for overcoming CRPC. The modification of melatonin (Mel) to a triphenylphosphonium (TPP) cation-targeted mitochondria-melatonin (Mito-Mel) significantly increases its potency by over 1000-fold. Mito-Mel selectively targets mitochondria, enhancing reactive oxygen species (ROS) generation and causing mitochondrial membrane potential disruption. This leads to the inhibition of mitochondrial respiration including the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), which, in turn, suppresses CRPC survival metabolic adaptations, such as glycolysis. In vitro and in vivo experiments reveal for the first time that natural small molecule compound with mitochondrial targeting via TPP exhibits excellent anticancer efficacy by inducing tumor cellular pyroptosis and facilitating the immune response, underlining the encouraging promise of this strategy for the effective treatment of CRPC.

Keywords: castration‐resistant prostate cancer; immune response; mito–melatonin; pyroptosis; tumor metabolism

DOI: https://doi.org/10.1002/smll.202408996

Biomedicines. 2025 Apr 09. pii: 909. [Epub ahead of print]13(4):

Comprehensive Integrated Analysis Reveals the Spatiotemporal Microevolution of Cancer Cells in Patients with Bone-Metastatic Prostate Cancer.

Yinghua Feng, Xiuli Zhang, Guangpeng Wang, Feiya Yang, Ruifang Li, Lu Yin, Dong Chen, Wenkuan Wang, Mingshuai Wang, Zhiyuan Hu, Yuan Sh, Nianzeng Xing.

Background/Objectives: Bone metastasis is a frequent and life-threatening event in advanced cancers, affecting up to 70-85% of prostate cancer patients. Understanding the cellular and molecular mechanisms underlying bone metastasis is essential for developing targeted therapies. This study aimed to systematically characterize the heterogeneity and microenvironmental adaptation of prostate cancer bone metastases using single-cell transcriptomics. Methods: We integrated the largest single-cell transcriptome dataset to date, encompassing 124 samples from primary prostate tumors, various bone metastatic sites, and non-malignant tissues (e.g., benign prostatic hyperplasia, normal bone marrow). After quality control, 602,497 high-quality single-cell transcriptomes were analyzed. We employed unsupervised clustering, gene expression profiling, mutation analysis, and metabolic pathway reconstruction to characterize cancer cell subtypes and tumor microenvironmental remodeling. Results: Cancer epithelial cells dominated the tumor microenvironment but exhibited pronounced heterogeneity, posing challenges for conventional clustering methods. By integrating genetic and metabolic features, we revealed key evolutionary trajectories of epithelial cancer cells during metastasis. Notably, we identified a novel epithelial subpopulation, NEndoCs, characterized by unique differentiation patterns and distinct spatial distribution across metastatic niches. We also observed significant metabolic reprogramming and recurrent mutations linked to prostate-to-bone microenvironmental transitions. Conclusions: This study comprehensively elucidates the mutation patterns, metabolic reprogramming, and microenvironment adaptation mechanisms of bone metastasis in prostate cancer, providing key molecular targets and clinical strategies for the precise treatment of bone metastatic prostate cancer.

Keywords: bone metastasis; metabolism and cytokines; prostate cancer; single-cell RNA sequencing; spatiotemporal microevolution

DOI: https://doi.org/10.3390/biomedicines13040909

Front Immunol. 2025 ;16 1576679

Advances in human microbiome and prostate cancer research.

Xin Pei, Lei Liu, Yuping Han.

Prostate cancer (PCa) is the second most common malignant tumor in men worldwide, and its metastatic and heterogeneous nature makes it significantly more difficult to treat. Recent studies have revealed the critical role of microbiota in PCa occurrence, progression, and treatment. Accumulating evidence from 16S rRNA and metagenomic sequencing suggests the presence of specific microbiota in prostate tissues and macrogenomics techniques: cancerous tissues are enriched with pro-inflammatory genera (e.g., Fusobacterium, Propionibacterium acnes), whereas commensal bacteria (e.g., Pseudomonas) are more common in paracancerous tissues. The microbiota drive tumor progression through activation of the NF-κB/STAT3 pathway to induce chronic inflammation, modulation of the immune microenvironment (e.g., Treg/Th17 imbalance and M2-type macrophage polarization), and metabolite (e.g., LPS, short-chain fatty acids)-mediated hormonal and epigenetic regulation. In terms of clinical translation, urinary microbiota characterization combined with metabolomics analysis may enhance diagnostic specificity, while gut flora modulation (e.g., probiotic interventions or fecal transplants) may improve resistance to androgen deprivation therapy. Current challenges include sequencing accuracy of low-biomass samples, limitations of causal mechanism validation models, and large cohort heterogeneity. In the future, it will be necessary to integrate multi-omics technologies to explore the bidirectional regulation of the "gut-prostate axis" and develop personalized therapeutic strategies targeting microorganisms. In this paper, we systematically review the interactions between microbiota and PCa and their clinical potentials to provide a theoretical basis for precision diagnosis and treatment.

Keywords: gut-prostate axis; microbiome; prostate cancer; tumor microenvironment; urinary microbiome

DOI: https://doi.org/10.3389/fimmu.2025.1576679