bims-meproc 2025-06-22 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–06–22
eleven papers selected by
Grigor Varuzhanyan, UCLA

Dietary saturated fatty acids and prostate cancer: insights into NF-κB pathway and lipid metabolism mechanisms.
Ezetimibe Engineered L14-8 Suppresses Advanced Prostate Cancer by Activating PLK1/TP53-SAT1-Induced Ferroptosis.
Fabiana imbricata Ruiz & Pav. (Solanaceae) essential oil analysis in prostate cancer cells: relevance of reactive oxygen species in proapoptotic activity.
Beta-blockers prolong response to androgen deprivation therapy in prostate cancer through modulation of the neuro-immuno-oncology axis.
RRP9 promotes prostate cancer metastasis and epithelial-mesenchymal transition through activation of the AKT/GSK3β/β-Catenin signaling pathway.
The association between waist-to-height index and prostate cancer risk: evidence from the NHANES study.
Integrative PANoptosis gene profiling reveals prognostic and therapeutic insights in prostate cancer.
Case series exploring hormonal sensitivity in prostate cancer patients harboring the germline African-ancestry HOXB13 X285K variant.
Pterostilbene Induces Apoptosis in Awakening Quiescent Prostate Cancer Cells by Upregulating C/EBP-β-Mediated SOD2 Transcription.
An integrated proteomic portrait of prostate cancer progression.
D-mannose augments targeted radioligand-immunotherapy of prostate cancer by enhancing radiosensitivity and reshaping immune microenvironment.

Discov Oncol. 2025 Jun 20. 16(1): 1166

Dietary saturated fatty acids and prostate cancer: insights into NF-κB pathway and lipid metabolism mechanisms.

Jia Wei He, Zi Xuan Huang, Yan Feng Su, Yang Qi Mo.

  Prostate cancer (PCa) is one of the most prevalent malignancies in men, with dietary factors, particularly saturated fatty acids (SFAs), emerging as significant contributors to its pathogenesis. This review synthesizes current literature linking dietary fat intake, especially from dairy products, to increased prostate cancer risk, highlighting specific SFAs such as myristic and palmitic acids. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is identified as a critical mediator in this relationship, promoting cell survival and proliferation in the tumor microenvironment. Additionally, the role of the lipogenic enzyme ELOVL7 is explored, emphasizing its involvement in fatty acid metabolism and cancer progression. While epidemiological and mechanistic studies provide compelling evidence for the link between dietary SFAs and prostate cancer through NF-κB activation, significant knowledge gaps remain, necessitating further research to elucidate the underlying mechanisms and potential therapeutic strategies targeting lipid metabolism.

Keywords:  Cancer progression.; Dietary factors; NF-κB pathway; Prostate cancer; Saturated fatty acids

DOI:  https://doi.org/10.1007/s12672-025-03005-0
Adv Sci (Weinh). 2025 Jun 19. e04192

Ezetimibe Engineered L14-8 Suppresses Advanced Prostate Cancer by Activating PLK1/TP53-SAT1-Induced Ferroptosis.

Yu Zhang, Xiao-Wen Song, Na Zhang, Xue-Hui Li, Fan-Chen Wu, Yu-Ang Wei, Dong-Liang Xu, Ling-Fan Xu, Fu-Wen Yuan.

  Androgen receptor signaling inhibitors (ARSIs) have demonstrated a survival benefit in metastatic prostate cancer. However, patients taking these agents inevitably acquire resistance and even develop neuroendocrine prostate cancer (NEPC), in which stage the AR signaling is inactive, and therapies are limited for these lethal cases. Therefore, developing novel treatments independent of the AR signaling pathway is urgently needed. Here it is reported that L14-8, a small molecule is derived and optimized from ezetimibe, a marketed drug primarily used for intestinal cholesterol and phytosterol absorption, significantly suppresses cell growth in advanced prostate cancer by inducing ferroptosis. Mechanistically, L14-8 binds to and promotes the ubiquitin-mediated PLK1 degradation, resulting in an increase of downstream TP53 protein phosphorylation, which is further enriched at the promoter of SAT1, a well-established ferroptosis inducer, and boosting SAT1 transcription thus triggers ferroptosis-mediated cancer cell death. Importantly, in vivo studies further demonstrate a potent anti-tumor efficacy of L14-8 without obvious toxicity. Overall, this study develops a novel small molecular engineered from ezetimibe for treating lethal prostate cancer in an AR-independent manner and provides mechanistic insights into its action by triggering PLK1-TP53-SAT1 axis-mediated ferroptosis in lethal PCa models independent of the AR signaling pathway.

Keywords:  SAT1; TP53; drug design and optimization; ferroptosis; prostate cancer

DOI:  https://doi.org/10.1002/advs.202504192
J Ethnopharmacol. 2025 Jun 16. pii: S0378-8741(25)00850-5. [Epub ahead of print] 120162

Fabiana imbricata Ruiz & Pav. (Solanaceae) essential oil analysis in prostate cancer cells: relevance of reactive oxygen species in proapoptotic activity.

Alejandro Madrid, Rosanna Avola, Adriana C E Graziano, Venera Cardile, Alessandra Russo.

ETHNOPHARMACOLOGICAL RELEVANCE: Fabiana imbricata Ruiz & Pav. (Solanaceae) is a Patagonian plant widely used in traditional medicine, in particular as a diuretic, digestive and for genito-urinary system diseases. Essential oils are considered promising candidates for prostate cancer treatments. Prostate cancer is the second leading cause of death among men. Therefore, new therapeutic strategies of prevention are needed for this tumor.
AIM OF THE STUDY: The present research was designed to explore the chemical composition of essential oil from fresh leaves of F. imbricata plants collected in Valparaíso region, Chile, and its activity on human prostate cancer cell lines.
MATERIALS AND METHODS: Chemical characterization was performed by chromatographic techniques and the biological activity was evaluated in androgen-sensitive (LNCaP) and androgen-insensitive (DU-145) human prostate cancer cell lines. The cells were exposed to essential oil for 72 hours and cell viability and cell membrane integrity were evaluated. Genomic DNA and caspase-3 activity was tested to confirm the cell death for apoptosis. Western blot analysis was employed to evaluate the expression of Bcl-2, Bax, cleaved caspase-3, cleaved caspase-9, SOD, Hsp70 and STAT-3 proteins. Assays to evaluate reactive oxygen species (ROS) and GSH levels were also performed.
RESULTS: The results showed the capacity of essential oil, for its active components (oxygenated sesquiterpenes, 77.54%), to reduce cell viability in prostate cancer cells. At a concentration of 200 μg/ml, the cell viability in LNCaP and DU-145 cells, was 23% and 26%, respectively. On the contrary, it showed no significant effect on normal cells, also at this high concentration. In addition, it induced apoptosis cell death, involving the downregulation of Hsp70 and STAT-3 proteins, correlated, at least in part, to an increase of reactive oxygen species (ROS).
CONCLUSIONS: This in vitro experimental preclinical study, suggesting a potential application of F. imbricata essential oil in prostate cancer, could be considered as a start point to design further research in animal experimental models and on its active components.

DOI: https://doi.org/10.1016/j.jep.2025.120162
J Transl Med. 2025 Jun 17. 23(1): 672

Beta-blockers prolong response to androgen deprivation therapy in prostate cancer through modulation of the neuro-immuno-oncology axis.

Malin Hagberg Thulin, Håkon Ramberg, Heidi Kristin Nielsen, Helene Hartvedt Grytli, Shivanthe Sivanesan, Abhilash D Pandya, Kotryna Seip, Kjetil Wessel Andressen, Anna Linder, Miriam Øijordsbakken, Matti Poutanen, Betina Katz, Bente Halvorsen, Gunhild Mari Mælandsmo, Kristin Austlid Taskén.

   BACKGROUND: The therapeutic impact of beta-blockers (BB), beta-adrenergic receptor antagonists, on prostate cancer remains controversial. The underlying health conditions of BB users complicate the ability to isolate and evaluate the specific effects of these drugs on the tumour cells. This study investigated whether BBs, by inhibiting sympathetic nerve signalling, extended the duration of androgen deprivation therapy (ADT) effectiveness in patients with de novo metastatic hormone sensitive prostate cancer and in prostate cancer xenograft models, while also uncovering the molecular mechanisms involved.
METHODS: An analysis was conducted on prospectively collected data from the Cancer Registry of Norway, Norwegian Prescription Database, and Norwegian Cause of Death Registry focusing on patients with de novo metastatic prostate cancer undergoing ADT using the commencement of second-line treatment as the endpoint. In addition, the causal effect of BB treatment was studied in two different hormone-sensitive prostate cancer xenograft mouse models. Prior to treatment, mice were surgically castrated, to mimic ADT, and tumour progression was tracked by measuring serum PSA levels. RNA sequencing was performed on xenografted orthotopic tumours to investigate the underlying mechanisms, utilizing annotation based on human data and protein levels were validated by the Protein Simple Immunoassay. Immune-related effects were evaluated using immunohistochemistry on tumour tissue and measuring neopterin levels, along with 92 analytes, using the OLINK proximity extension assay on serum samples from xenografted mice and prostate cancer patients, both BB users and non-users.
RESULTS: A competitive risk analysis indicated that BB treatment postponed the initiation of second-line treatment in prostate cancer patients on ADT. Additionally, in both prostate cancer xenograft models, BB treatment reduced tumour burden and delayed progression to castration-resistant prostate cancer. Mechanistically, BB treatment suppressed androgen receptor signalling and induced a metabolic shift by up-regulating oxidative phosphorylation transcripts and down-regulating those involved in fatty acid synthesis and the PI3K/AKT/mTOR pathway. Additionally, BB treatment increased serum pro-inflammatory cytokines, such as the IL23/IL17 axis, in both xenografted mice and in patient samples. Enhanced intra-tumoral CD68+ immune cell infiltration was also observed in the tumours.
CONCLUSION: The data suggest that BB combined with ADT delay the progression to castration-resistant prostate cancer. This may be achieved by influencing androgen receptor activity, adjusting energy metabolism and fostering a pro-inflammatory antitumoral microenvironment.

Keywords:  Androgen receptor; Beta-adrenergic receptor; Castration-resistant prostate cancer; Oxidative phosphorylation; PI3K/AKT/mTOR; Pro-inflammatory; SRC

DOI:  https://doi.org/10.1186/s12967-025-06644-7
Discov Oncol. 2025 Jun 17. 16(1): 1129

RRP9 promotes prostate cancer metastasis and epithelial-mesenchymal transition through activation of the AKT/GSK3β/β-Catenin signaling pathway.

Zijian Da, Yadan Du, Yawen Chen, Mingxu Da, Fenghai Zhou.

  Ribosomal RNA Processing 9 (RRP9) is a gene associated with ribosomal function, and studies have demonstrated that its expression is aberrantly regulated in various tumor types, correlating with tumor progression. However, the specific role and underlying mechanism of RRP9 in prostate cancer (PCa) remain largely unexplored. In this study, bioinformatics analysis revealed that RRP9 is upregulated in PCa and is significantly associated with poor prognosis and lymph node metastasis. Further experimental data demonstrated that RRP9 knockdown notably inhibited the metastasis, invasion, and epithelial-mesenchymal transition (EMT) of PCa. Conversely, overexpression of RRP9 activated the AKT signaling pathway, resulting in the phosphorylation of GSK3β at Ser9, which in turn prevented β-catenin degradation and promoted cell metastasis, invasion, and EMT. Rescue experiments demonstrated that SC79 effectively reversed the inhibitory effects of RRP9 knockdown on PCa. These findings highlight the potential role of RRP9 in promoting the malignant biological behaviors of PCa, providing new insights and potential therapeutic strategies for the treatment of the disease.

Keywords:  AKT; Epithelial-mesenchymal transition; GSK3β; Metastasis; Prostate cancer; RRP9; β-catenin

DOI:  https://doi.org/10.1007/s12672-025-02833-4
Front Nutr. 2025 ;12 1610288

The association between waist-to-height index and prostate cancer risk: evidence from the NHANES study.

Qinghe Gao, Zongqi Lin, Yihua Zhang, Jiantong Cai, Shaopeng Li.

   Background: Prostate cancer (PCa) is associated with obesity, especially visceral fat. WWI may reflect the distribution of body fat more accurately. However, it is unclear whether WWI is associated with the risk of developing PCa.
Methods: Seventy thousand one hundred and ninety participants took part in the National Health and Nutrition Examination Survey (NHANES). The associations between WWI and PCa risk were analyzed through multiple regression. The association between WWI and prostate cancer was analyzed in subgroups using stratified factors, with interaction tests performed to evaluate the stability of this association across subgroups. In addition, restricted cubic sample plots and threshold effects were examined to further explore the nonlinear association between WWI and prostate cancer. Finally, subject work characteristics (ROC) curves were used to evaluate the accuracy of different obesity indicators in predicting PCa.
Results: Multiple regression analyses revealed that those individuals with a higher WWI index had a higher prevalence of prostate cancer, while subgroup analyses and interaction tests showed that the correlation between WWI and the prevalence of PCa differed across age groups (interaction p < 0.05). The ROC curves showed that the predictive power of WWI for the prevalence of PCa was superior to that of traditional indicators of obesity (both p < 0.05).
Conclusion: There was a positive and significant association between PCa risk and WWI, especially in male participants aged <60 years. Further comprehensive studies are required to confirm our findings.

Keywords:  NHANES; PCA; ROC curve; WWI; abdominal obesity; visceral fat

DOI:  https://doi.org/10.3389/fnut.2025.1610288
Biomol Biomed. 2025 Jun 19.

Integrative PANoptosis gene profiling reveals prognostic and therapeutic insights in prostate cancer.

Yi Wang, Yiheng Du, Xizhi Wang, Jiang Yu, Qing Gu, Guangquan Yuan, Yifei Zhu, Liyang Gu, Jun Ouyang.

Prostate cancer (PCa) remains a significant global health challenge, representing the most common solid tumor in men and the fifth leading cause of cancer-related death. Despite therapeutic advances, achieving a definitive cure remains difficult. Early diagnosis and personalized treatment strategies are crucial for improving patient outcomes. Programmed cell death-particularly PANoptosis, an inflammatory pathway that integrates pyroptosis, apoptosis, and necroptosis-has emerged as a promising therapeutic target in oncology. In this study, individuals with PCa were categorized into PANoptosis-high and PANoptosis-low subgroups based on the expression levels of 45 PANoptosis-related genes. Differential gene expression analysis and subsequent enrichment analyses were conducted to explore the biological pathways associated with each subgroup. A four-gene risk signature (CASP7, ADAR, DNM1L, and NAIP) was identified, showing strong predictive value for overall survival (OS) in both training and validation cohorts. This signature was independently associated with OS and showed meaningful correlations with the tumor microenvironment, particularly immune cell infiltration and immunotherapy responsiveness. These findings suggest that the PANoptosis-related gene signature may serve as a valuable prognostic biomarker and inform immunotherapeutic strategies in PCa management.

DOI: https://doi.org/10.17305/bb.2025.11998
Prostate Cancer Prostatic Dis. 2025 Jun 21.

Case series exploring hormonal sensitivity in prostate cancer patients harboring the germline African-ancestry HOXB13 X285K variant.

Mayuko Kanayama, Emeline Colomba, Yusra Shao, Sarah M Nielsen, Edward D Esplin, Changxue Lu, William B Isaacs, John C Henegan, Elisabeth I Heath, Jun Luo, Régine Marlin, Emmanuel S Antonarakis.

BACKGROUND: Recently, a germline HOXB13 variant, X285K was identified as a risk factor for prostate cancer in men of African ancestry. While this variant is likely associated with more aggressive prostate cancer, there has not yet been an in-depth clinical description of individual patients carrying this variant and their response to systemic therapies.
METHODS: We studied six cases of germline X285K carriers with metastatic hormone-sensitive prostate cancer to characterize their hormonal sensitivity or resistance.
CONCLUSIONS: Longitudinal outcome analysis indicates that patients carrying X285K generally show favorable responses to therapies targeting the androgen receptor (AR), a finding that requires confirmation.

DOI: https://doi.org/10.1038/s41391-025-00994-5
Int J Biol Sci. 2025 ;21(8): 3379-3396

Pterostilbene Induces Apoptosis in Awakening Quiescent Prostate Cancer Cells by Upregulating C/EBP-β-Mediated SOD2 Transcription.

Zhichao Xi, Mengfan Liu, Xue Jiang, Jiling Feng, Rongchen Dai, Wan Najbah Nik Nabil, Xueyang Sun, Jiayi Chen, Hangui Ren, Juan Zhang, Qihan Dong, Man Yuan, Yang Li, Hongxi Xu.

  Quiescent cancer cells (QCCs) are known to resist chemoradiotherapy, evade immune surveillance and have the potential to drive recurrence years after initial treatment. However, the key regulators of QCC survival during reactivation remain unclear. This study revealed that superoxide dismutase 2 (SOD2) levels are significantly greater in quiescent prostate cancer (PCa) cells than in proliferative cells. SOD2 overexpression induces apoptosis in awakening quiescent PCa cells, whereas its knockdown promotes reactivation. Elevated SOD2 also suppresses recurrent tumor growth by quiescent PCa cells and prolongs survival. Pterostilbene (PTE), a natural compound, preferentially induces apoptosis in quiescent PCa cells during awakening and reduces their long-term proliferative capacity by upregulating SOD2. Additionally, PTE inhibits tumorigenesis and significantly reduces the growth of quiescent PCa cells without apparent toxicity. Further mechanistic studies revealed that CCAAT/enhancer-binding protein beta (C/EBP-β) is critical for PTE-mediated SOD2 upregulation by enhancing SOD2 transcription. C/EBP-β knockdown significantly reduces PTE-induced apoptosis in awakening quiescent PCa cells. Clinical analysis revealed a positive correlation between CEBPB and SOD2, with low C/EBP-β expression linked to poor prognosis. Overall, the C/EBP-β-SOD2 pathway is crucial for eliminating awakening quiescent PCa cells and highlights PTE as a promising agent for preventing PCa recurrence.

Keywords:  Apoptosis; C/EBP-β; Prostate cancer recurrence; Pterostilbene; Quiescent cancer cells; SOD2

DOI:  https://doi.org/10.7150/ijbs.106219
Cell Rep. 2025 Jun 13. pii: S2211-1247(25)00599-6. [Epub ahead of print]44(6): 115828

An integrated proteomic portrait of prostate cancer progression.

Jichang Zhang, Keith D Rivera, Daniela Bossi, Federico Gianfanti, Simone Nicastri, Diana Gomes, Milos Matkovic, Marco Coazzoli, Simone Mosole, Federico Costanzo, Arianna Vallerga, Valentina Ceserani, Manuela Cavalli, Maya Virshup, Rajan A Burt, Marco Bolis, Dorothea Ruthishauser, Anastasios Stathis, Holger Moch, Lukas Bubendorf, Andrea Cavalli, Eva Corey, Yuzhuo Wang, D R Mani, Steven A Carr, Namrata Udeshi, Jean-Philippe Theurillat.

  Cancer forms a local tumor that subsequently metastasizes to distant organs. In prostate cancer, the latter part of the trajectory is influenced by the inhibition of the androgen receptor (AR). The study of proteomic changes along disease progression may reveal insights into how prostate cancer evolves and open new therapeutic avenues. Here, we profile changes in protein abundance and post-translational modifications (PTMs) along the disease trajectory in patient-derived xenograft models. Our results suggest new therapeutic opportunities, such as USP1 inhibition and a key early involvement of the receptor tyrosine kinase (RTK)-RAS-mitogen-activated protein kinase (MAPK) pathway during disease progression. We highlight multiple alterations within the latter, including the tumor suppressors NF1 and ERF. Specific PTMs suggest changes in mitochondrial ATP synthesis, proteasomal activity, gene splicing, and transforming growth factor beta (TGF-β) signaling. Finally, we show how different transcription factors engage with disease progression. A web resource is provided, enabling the investigation of proteomic resources.

Keywords:  CP: Cancer; MAPK pathway; acetylation; castration-resistant prostate cancer; disease progression; lineage plasticity; prostate cancer; protein phosphorylation; resistance to androgen receptor inhibition; ubiquitylation

DOI:  https://doi.org/10.1016/j.celrep.2025.115828
Drug Deliv Transl Res. 2025 Jun 14.

D-mannose augments targeted radioligand-immunotherapy of prostate cancer by enhancing radiosensitivity and reshaping immune microenvironment.

Lei Tao, Bin Xu, Juan Sun, Jiangtao Yang, Fenghua Meng, Zhiyuan Zhong.

  Targeted radioligand therapy (TRT) is an emerging therapeutic modality for advanced tumors like metastatic castration-resistant prostate cancer. The patients bare, however, varying degrees of resistance to TRT, which would greatly lessen the treatment efficacy and response rate. Here, we find that oral medication of D-mannose effectively enhances the radiosensitivity of PSMA-positive murine RM1-hPSMA prostate cancer cells to TRT by suppressing glucose metabolism. This metabolic disruption not only impeded the proliferation of RM1-hPSMA cells but also augmented DNA damage within tumor cells subjected to TRT, co-promoting cell apoptosis. Interestingly, TRT-D-mannose combination strongly boosted the anti-tumor immune responses by inducing immunogenic cell death, disrupting the immune evasion mechanisms employed by tumor cells, and reducing immunosuppressive cells in the tumor. D-mannose significantly improved the TRT efficacy for highly aggressive murine RM1-hPSMA and human LNCaP Clone FGC models, without causing adverse effects. Hence, D-mannose is potentially a safe radio-sensitizer and a potent immune activator for TRT.

Keywords:  Immune response; Prostate cancer; Radio-sensitizer; Targeted radioligand therapy; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13346-025-01886-w