bims-meproc 2025-07-13 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–07–13
twelve papers selected by
Grigor Varuzhanyan, UCLA

Inhibition of the PI3K/AKT signaling pathway blocks the oncogenic activity of TRIM26 in prostate cancer cells.
Synergistic Inhibition of Prostate Cancer Progression in Mice With a Combination of Curcumin and Ursolic Acid in the Diet.
Mechanisms underlying prostate cancer sensitivity to reactive oxygen species: overcoming radiotherapy resistance and recent clinical advances.
Androgen induces 3'UTR shortening of de novo lipogenesis genes by alternative polyadenylation in prostate cancer cells.
HIF1α-PHD1-FOXA1 Axis Orchestrates Hypoxic Reprogramming and Androgen Signaling Suppression in Prostate Cancer.
Nop2/Sun domain family member 5 contributes to tumorigenic properties in prostate cancer by engaging the PI3K-AKT pathway and tumor-associated macrophages.
Endoplasmic Reticulum Stress-Driven Nucleotide Catabolism Fuels Prostate Cancer.
Untargeted metabolomics revealed urinary metabolic pattern for discriminating prostate cancer from benign prostatic hyperplasia in Chinese participants.
Thieno[2,3-b]pyridine compounds potently inhibit prostate cancer growth and motility.
Loss of ATG5 expression in a subset of human prostate cancers promotes tumor growth through accumulation of p62.
Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review).
Diagnostic Accuracy of [18F]-DCFPyL PSMA PET/CT in Intermediate-Risk Prostate Cancer Undergoing Radical Prostatectomy: Is Pelvic Lymph Node Dissection Still Necessary?

Asian J Androl. 2025 Jul 08.

Inhibition of the PI3K/AKT signaling pathway blocks the oncogenic activity of TRIM26 in prostate cancer cells.

Yue-Ya Zhong, Li-Huan Zhang, Xin-Ye Zhou, Xiu-Min Zhou, Yuan-Ming He, Xin-Liang Mao, Xiao-Feng Xu.

   ABSTRACT: The tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase with strong oncogenic activity in various cancers. However, its role and molecular mechanism in prostate cancer (PCa) remain elusive. To clarify its role in promoting PCa progression, we evaluated TRIM26 expression in cells and clinical specimens using immunohistochemistry and found that TRIM26 was significantly upregulated in PCa tissue. Moreover, high TRIM26 levels predicted a poor prognosis in patients with PCa. Ectopic overexpression of TRIM26 increased PCa cell proliferation and migration, and this activity was suppressed by TRIM26 knockdown. Notably, TRIM26 activated both protein kinase B (AKT)/mammalian target of the rapamycin (mTOR) and the epithelial-mesenchymal transition (EMT) signaling pathways in PCa cells. Consistent with these findings, TRIM26 knockdown led to decreased activation of these signals. Furthermore, the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway activated by TRIM26 was attenuated by the PI3K inhibitor S14161. Similarly, cisplatin, a commonly used anti-PCa drug, downregulated TRIM26 and AKT/mTOR activation, while TRIM26 overexpression reversed AKT/mTOR inactivation. Finally, this finding was also demonstrated TRIM26 expression strikingly promoted tumor growth and activated AKT/mTOR signaling in a PCa xenograft. In conclusion, TRIM26 drives PCa malignancy and may be an attractive target for PCa treatment.

Keywords:  PI3K/AKT/mTOR signaling pathway; TRIM26; prostate cancer

DOI:  https://doi.org/10.4103/aja202526
Mol Carcinog. 2025 Jul 06.

Synergistic Inhibition of Prostate Cancer Progression in Mice With a Combination of Curcumin and Ursolic Acid in the Diet.

Chelsea A Friedman, Achinto Saha, Rachel Clark, Carly Wilder, Jordan Wright, John DiGiovanni.

  Prostate cancer (PCa) is the second leading cause of cancer-related death among American men, and its long latency offers a window for chemopreventive strategies. Phytochemicals, with their diverse impacts on cancer cell growth and metabolism, represent promising candidates for such strategies. Combining compounds like curcumin (Curc) and ursolic acid (UA), which target multiple pathways, can be advantageous in slowing tumor progression. Previous studies revealed the synergistic effects of Curc + UA in reducing tumor growth in a PCa allograft model. In this study, diet-based interventions were evaluated using two transgenic mouse models of PCa. Mice fed a Curc + UA-enriched diet exhibited significant inhibition of prostate tumor progression compared to single-agent diets in both HiMyc and PTEN knockout mouse models. Protein analyses of ventral prostate tissues from HiMyc mice indicated that the combination suppressed oncogenic signaling pathways, including STAT3, AKT, and mTORC1, while modulating cell regulatory proteins to inhibit tumor cell proliferation. Furthert mechanistic studies in mouse and human PCa cell lines confirmed that Curc + UA exerted pleiotropic effects by influencing oncogenic signaling, cell cycle regulation, mitochondrial function, unfolded protein response (UPR), and apoptosis, collectively contributing to its synergistic efficacy. These findings highlight the potential of Curc + UA to inhibit PCa progression through multitargeted mechanisms. The combination's superior efficacy over single agents underscores its promise as a chemopreventive or therapeutic strategy. This study provides a strong rationale for further mechanistic investigations and clinical development of Curc + UA for PCa prevention and treatment.

Keywords:  HiMyc mice; PTEN KO mice; cell cycle; chemoprevention; oncogenic signaling

DOI:  https://doi.org/10.1002/mc.70000
Cancer Biol Med. 2025 Jul 10. pii: j.issn.2095-3941.2024.0584. [Epub ahead of print]

Mechanisms underlying prostate cancer sensitivity to reactive oxygen species: overcoming radiotherapy resistance and recent clinical advances.

Meidan Wang, Rui Xing, Liqun Wang, Mingyue Pan, Ruoyun Zhang, Ting Li, Weiqiang Sun, Jing Zhou.

  Prostate cancer (PCa) is a leading cause of cancer-related mortality among men. Radiotherapy is the cornerstone of PCa treatment. However, a major limitation of radiotherapy is the development of resistance, which compromises treatment efficacy. Reactive oxygen species (ROS), which are generated by radiation, have a dual role in PCa by inducing DNA damage and apoptosis, while also promoting tumor progression and radioresistance. Elevated ROS levels enhance metabolic reprogramming, activate oncogenic pathways, and influence the tumor microenvironment by modulating immune responses and promoting the epithelial-mesenchymal transition (EMT). Key molecular mechanisms, including the Nrf2/Keap1 signaling axis, Bcl-2 mutations, and Speckle-type POZ protein alterations, contribute to radioresistance by enhancing antioxidant defenses and DNA repair capacity. Additionally, the interplay between hypoxia, androgen receptor variants (AR-Vs), and ferroptosis regulators further influence radiotherapy outcomes. Understanding these resistance mechanisms is crucial for developing targeted strategies to enhance radiosensitivity and improve therapeutic outcomes in PCa patients.

Keywords:  Prostate cancer (PCa); antioxidants; radiation therapy (RT); radiotherapy resistance; reactive oxygen species (ROS)

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2024.0584
Sci China Life Sci. 2025 Jul 08.

Androgen induces 3'UTR shortening of de novo lipogenesis genes by alternative polyadenylation in prostate cancer cells.

Wei-Jie Sun, Fei Liang, Hui Zhao, Yun-Mei Wang, Zhong-Yin Zhou, Hui Xu, Hang Liu, Dong Tang, An-Long Xu, Yong-Gui Fu, Xi Li, Jun Ouyang, Newton O Otecko, Ben-Xia Hu, Teng-Fei Ma, Xin Li, Dong-Dong Wu, Hui Zhao, Ya-Ping Zhang.

  Alternative polyadenylation (APA) is a pervasive mechanism that is emerging as a formidable player in post-transcriptional regulation. The transcriptional landscape can be altered via APA in response to various stimulating factors. Using the PacBio single-molecule long-read sequencing method, we present for the first time the 3'UTR landscape and reveal a global increase of APA events in prostate cancer (PCa) LNCaP cells in response to androgen dihydrotestosterone (DHT), a critical regulator of PCa progression. With evidence from differential gene expression analyses of Illumina RNA-sequencing data, we demonstrated that genes with DHT-induced changes in both expression and APA were enriched in lipid metabolism. These genes predominantly supported de novo fatty acid synthesis, such as FASN and ACSL3. Furthermore, we showed that an isoform switch to the proximal poly(A) site of these genes depended on the androgen receptor, and the expression of cancer-associated genes was upregulated by the escape of miRNA-regulated repression machinery. To address the role of key gene shortening in PCa, we prepared 22RV1-FS cells missing the distal poly(A) signal of FASN in the AR+ PCa cell line 22RV1 using CRISPR/Cas9 technology. As expected, the edited 22RV1-FS cells overexpressed FASN mRNA and protein and were inclined to cell proliferation in vitro and tumorigenesis in vivo. Interestingly, we found that FASN transcripts with a shortened 3'UTR were significantly increased in advanced PCa and castration-resistant prostate cancer compared with benign prostate hyperplasia, suggesting a possible association between usage of the proximal poly(A) site and disease progression. Therefore, our study highlights the importance of the APA mechanism in response to DHT stimulation in PCa cells and provides a novel regulatory mechanism through which DHT-induced APA causes altered expression of de novo lipogenesis genes, with a possible association with the progression of PCa.

Keywords:   FASN ; de novo lipogenesis gene; APAome; alternative polyadenylation; androgen; prostate cancer

DOI:  https://doi.org/10.1007/s11427-024-2740-7
Cells. 2025 Jul 02. pii: 1008. [Epub ahead of print]14(13):

HIF1α-PHD1-FOXA1 Axis Orchestrates Hypoxic Reprogramming and Androgen Signaling Suppression in Prostate Cancer.

Limiao Liang, Dandan Dong, Jiaxue Sun, Qin Zhang, Xiayun Yang, Gong-Hong Wei, Peng Zhang.

  Hypoxia is a hallmark of aggressive prostate cancer, but how it disrupts lineage-specific transcriptional programs to drive progression remains unclear. Here, we identify the HIF1α-PHD1-FOXA1 axis as a critical mediator of hypoxic adaptation and androgen signaling suppression. Using genome-wide profiling, we demonstrate that hypoxia reprograms HIF1α chromatin occupancy, shifting its cooperation from AR to FOXA1. Mechanistically, HIF1α physically interacts with FOXA1, destabilizing it via PHD1-mediated hydroxylation-a previously unrecognized post-translational regulatory node. Under hypoxia, loss of FOXA1 attenuates androgen-responsive transcription while activating hypoxia-inducible genes, demonstrating a dual role for this axis in hypoxia adaptation and prostate cancer progression. Genetic or pharmacological disruption of HIF1α-PHD1-FOXA1 impairs prostate cancer proliferation and migration, underscoring its translational relevance. Our findings establish oxygen-dependent FOXA1 degradation as a linchpin connecting microenvironmental stress to transcriptional plasticity in advanced prostate cancer, offering new therapeutic avenues.

Keywords:  FOXA1; HIF1α; PHD1; cistrome reprogramming; prostate cancer

DOI:  https://doi.org/10.3390/cells14131008
Biochim Biophys Acta Mol Basis Dis. 2025 Jul 07. pii: S0925-4439(25)00322-9. [Epub ahead of print]1871(7): 167974

Nop2/Sun domain family member 5 contributes to tumorigenic properties in prostate cancer by engaging the PI3K-AKT pathway and tumor-associated macrophages.

Mengjun Huang, Hailin Zou, Yufan Liang, Fei Cao, Qiliang Teng, Yupeng Guan, Yiting Wang, Jun Pang, Hanqi Lei.

   PURPOSE: Nop2/Sun domain family member 5 (NSUN5), a member of the m5C methylation family, plays a critical role in various biological processes by influencing RNA stability and regulating gene expression. The main purpose of this study was to determine the specific role of NSUN5 in prostate cancer (PCa) progression.
METHODS: TCGA-PRAD database was used to analyze the differential expression of NSUN5 between PCa and normal tissues, as well as its association with survival outcomes, signaling pathways, and immune infiltration. Subsequently, immunohistochemistry was performed to evaluate NSUN5 expression in PCa tissues. Functional assays, including gain- and loss-of-function experiments, were conducted to explore the effects of NSUN5 on PCa cell proliferation, migration, and the expression of key proteins in relevant signaling pathways. Cell co-culture, in vivo experiments, and flow cytometry analysis were used to explore the effects of NSUN5 on macrophage polarization and the immune microenvironment of PCa.
RESULTS: NSUN5 is significantly overexpressed in PCa tissues and is positively correlated with advanced disease stages and poor patient prognosis. Functionally, NSUN5 enhances in vitro proliferation and migration, as well as in vivo tumor growth, primarily through activation of the PI3K-AKT signaling pathway. Moreover, NSUN5 facilitates the polarization of macrophages into tumor-associated macrophages within PCa tissues, thereby contributing to immune evasion.
CONCLUSION: NSUN5 promotes PCa progression through the PI3K-AKT pathway and induces macrophage polarization toward a pro-tumor phenotype, promoting the formation of a suppressive tumor microenvironment.

Keywords:  NSUN5; PI3K-AKT; Prostate cancer; Therapeutic target; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.bbadis.2025.167974
Cancer Lett. 2025 Jul 03. pii: S0304-3835(25)00456-2. [Epub ahead of print] 217888

Endoplasmic Reticulum Stress-Driven Nucleotide Catabolism Fuels Prostate Cancer.

Ke Deng, Nora Pällmann, Marte Livgård, Wanja Kildal, Manohar Pradhan, Ladan Fazli, Paul S Rennie, Yang Jin, Fahri Saatcioglu, Omer Kuzu.

Endoplasmic reticulum (ER) stress is a critical regulator of cancer cell metabolism and survival. In this study, we elucidate the coordinated roles of two key ER stress mediators, Activating Transcription Factor 4 (ATF4) and X-box Binding Protein 1 spliced (XBP1s), in regulating purine homeostasis in prostate cancer (PCa) cells. We demonstrate that ATF4 directly upregulates Molybdenum Cofactor Sulfurase (MOCOS), a key enzyme in purine catabolism, while XBP1s induces the expression of xanthine dehydrogenase (XDH), the principal MOCOS target in this pathway. Knockdown of MOCOS significantly impairs PCa cell proliferation as well as prostatosphere and colony formation in vitro and inhibits tumor growth in preclinical mouse models of PCa. Mechanistically, MOCOS suppression leads to purine accumulation, disrupts pyrimidine synthesis, and causes nucleotide imbalance, resulting in replication fork stalling. This imbalance is also accompanied by a compromised glutathione-mediated antioxidant response, rendering the cells more susceptible to DNA damage. Importantly, targeting XDH, either genetically or biochemically, also significantly hinders PCa cell growth. Collectively, our data highlight the pivotal role of ER stress-mediated purine homeostasis in sustaining PCa cell growth.

DOI: https://doi.org/10.1016/j.canlet.2025.217888
Front Oncol. 2025 ;15 1604169

Untargeted metabolomics revealed urinary metabolic pattern for discriminating prostate cancer from benign prostatic hyperplasia in Chinese participants.

Chenye Tang, Xiao Guo, Qian Zou, Xinghao Wang, Jian Sheng, Dan Shen, Chun Sun, Shuo Li, Ruilin Shen.

   Introduction: Precise screening and discriminating of prostatic hyperplasia (PH) could avoid unnecessary biopsy and overdiagnosis. However, the metabolic pattern of patients with prostatic hyperplasia in Chinese population is rarely reported.
Methods: Urine samples of Chinese participants with prostate cancer (PCa), benign prostatic hyperplasia (BPH) and non-prostate diseases (NPD) were detected with four ultra-performance liquid chromatography/tandem mass spectrometric (UPLC-MS/MS) methods to profile the metabolic disturbance.
Results: In patients with PH, the most significant dysregulation was observed in metabolites categorized as lipid or amino acid, especially those involved in histidine metabolism, purine metabolism, tryptophan metabolism and tyrosine metabolism. For discrimination BPH from PCa, apart from previously reported metabolites related to phospholipid metabolism or tryptophan metabolism, metabolites of dipeptides and androgenic steroids, such as leucylhydroxyproline and etiocholanolone glucuronide, also exhibited potential to discriminate PCa from BPH.
Conclusion: This study conducts precise detection of urinary metabolomic pattern for patients with benign prostatic hyperplasia or prostate cancer, and could inform their potential application as discriminant biomarkers.

Keywords:  discriminant biomarkers; prostate cancer; prostatic hyperplasia; untargeted metabolomics; urinary metabolomics

DOI:  https://doi.org/10.3389/fonc.2025.1604169
Endocr Oncol. 2025 Jan;5(1): e240082

Thieno[2,3-b]pyridine compounds potently inhibit prostate cancer growth and motility.

M A Alkheilewi, D A Leach, A Mohr, R M Zwacka, P Laissue, M Metodiev, C L Bevan, M Van Rensburg, L I Pilkington, D Barker, J Reynisson, G N Brooke.

   Objective: Prostate cancer growth is dependent upon androgens and hence therapies often target this signalling axis. These therapies, for example the antiandrogen enzalutamide, are successful in the majority of men; however, resistance is inevitable and the tumour progresses to the castrate-resistant stage, a disease of unmet clinical need. Consequently, there is a great need for novel therapeutics for castrate-resistant prostate cancer. Thieno[2,3-b]pyridine compounds have shown promise as novel anti-cancer molecules, but little is known about their efficacy in prostate cancer. To address this, a panel of thieno[2,3-b]pyridine compounds was screened to identify those with cytostatic/cytotoxic activity in prostate cancer.
Methods: The effect of the compounds upon prostate cancer proliferation and motility was assessed in a panel of cell lines representing different stages of the disease and non-tumorigenic controls. The effect of the compounds upon cell morphology and cell death was assessed using imaging and flow cytometry, respectively. The efficacy of the lead compound was also assessed in a patient-derived explant model.
Results: The compounds were found to inhibit prostate cancer proliferation and motility, promote G2/M arrest, multinucleation and apoptosis. Importantly, treatment of patient-derived explants with the lead compound DJ160 demonstrated that the molecule inhibits prostate cancer proliferation, even in samples that appear to be resistant to enzalutamide.
Conclusions: Thieno[2,3-b]pyridines therefore represent a potential therapy for prostate cancer, even when current therapies have failed.

Keywords:  multinucleation; prostate cancer; therapeutics; therapy resistance

DOI:  https://doi.org/10.1530/EO-24-0082
bioRxiv. 2025 May 08. pii: 2025.05.02.651776. [Epub ahead of print]

Loss of ATG5 expression in a subset of human prostate cancers promotes tumor growth through accumulation of p62.

Daric J Wible, Wen Jess Li, Xiaozhuo Liu, Manu M Sebastian, Dean G Tang, Shawn B Bratton.

Loss-of-function mutations in autophagy-related (ATG) genes are rare in cancer. However, we report herein that ATG5 is fully deleted in ∼14% of prostate cancers (PCa), rivaling that of well-established tumor suppressor genes. ATG5 expression was downregulated at both mRNA and protein levels and was associated with poor patient survival. The DU145 PCa cell line, isolated from a brain metastasis, is entirely deficient in ATG5; and while ATG5 reintroduction restored autophagy, it dramatically inhibited tumor growth in vivo and led to near complete consumption of the multifunctional autophagy receptor/signaling protein, p62. Deletion of SQSTM1 confirmed that p62 was essential for tumor growth; and Reverse Phase Protein Array analysis revealed that p62 protein was significantly increased in prostate tumors, despite a reduction in mRNA expression. Thus, ATG5 appears to function as a novel tumor suppressor in a subset of prostate tumors and does so, at least in part, through autophagic degradation of p62.

DOI: https://doi.org/10.1101/2025.05.02.651776
Oncol Rep. 2025 Sep;pii: 109. [Epub ahead of print]54(3):

Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review).

Yun-Fan Li, Shuai Su, Yu Luo, Chengcheng Wei, Jingke He, Liang-Dong Song, Kun Han, Jue Wang, Xiangzhi Gan, De-Lin Wang.

  Neuroendocrine (NE) prostate cancer (NEPC) is an aggressive and lethal subtype of prostate cancer. It is typically characterized by the expression of NE markers and the loss of androgen receptor expression. De novo NEPC is rare, accounting for <2% of all prostate cancer cases at diagnosis. More commonly, NEPC arises from prostate adenocarcinoma following androgen deprivation therapy, with 20‑25% of metastatic castration‑resistant prostate cancers undergoing NE differentiation due to lineage plasticity. During this transition, pathways associated with epithelial‑mesenchymal transition (EMT) and stemness are broadly activated, which is considered to be a key driver of NEPC's high metastatic potential, resistance to chemotherapy and radiotherapy and poor prognosis. EMT facilitates metastasis by enhancing cellular motility and invasiveness, while stemness properties contribute to post‑metastatic colonization, immune evasion, therapy resistance and cellular dormancy. As manifestations of cellular plasticity, these processes share overlapping molecular mechanisms. Targeting key regulators within these pathways may offer promising therapeutic strategies for NEPC.

Keywords:  epithelial‑mesenchymal transition; molecular mechanism androgen signaling; neuroendocrine prostate cancer; stemness

DOI:  https://doi.org/10.3892/or.2025.8942
J Urol. 2025 Jul 07. 101097JU0000000000004659

Diagnostic Accuracy of [18F]-DCFPyL PSMA PET/CT in Intermediate-Risk Prostate Cancer Undergoing Radical Prostatectomy: Is Pelvic Lymph Node Dissection Still Necessary?

Ahmed Eraky, Neeraja Tilu, Reuben Ben-David, Brenda Hug, Henry Jodka, Yashaswini Agarwal, Hannah Sur, Ming Zhou, Manish Kumar Choudhary, Reza Mehrazin, Ashutosh Tewari.

   PURPOSE: Pelvic lymph node dissection (PLND) remains standard for nodal staging in prostate cancer (PCa), yet its benefit in intermediate-risk PCa is controversial. Traditional imaging and nomograms often lack accuracy, resulting in unnecessary PLND. Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) is a promising alternative. We compared its diagnostic performance and clinical utility with established risk models in intermediate-risk PCa.
MATERIALS AND METHODS: We analyzed intermediate-risk PCa patients who underwent [18F]-DCFPyL PSMA PET/CT and radical prostatectomy with bilateral PLND between January 2022 and December 2023. PSMA PET/CT results were classified as positive or negative for nodal involvement. Diagnostic performance was compared to multiparametric magnetic resonance imaging (mpMRI), the Briganti 2012, Briganti 2023 nomograms and the Memorial Sloan Kettering Cancer Center nomogram by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, balanced accuracy, and area under the curve (AUC).
RESULTS: Among 189 patients, 28 (15%) had PSMA-positive lymph nodes. Pathology confirmed metastases in 4 PSMA-positive patients (PPV: 14%, 95%CI: 7.1-22%) and 1 PSMA-negative patient (NPV: 99%, 95%CI: 98-100%). PSMA PET/CT demonstrated 80% sensitivity (95%CI: 40-100%), 87% specificity (95%CI: 82-91%), balanced accuracy of 83% (95%CI: 63-95%), and an AUC of 0.83 (95%CI: 0.64-1), outperforming other models. PSMA would have safely omitted PLND in 160 of 161 (99%) PSMA-negative cases, while mpMRI detected no positive nodes.
CONCLUSIONS: PSMA PET/CT, with high specificity and NPV, may safely guide PLND omission in PSMA-negative patients. Prospective validation is warranted.

Keywords:  Intermediate-Risk; Lymph Node Dissection; PET/CT; PSMA; Prostate Cancer

DOI:  https://doi.org/10.1097/JU.0000000000004659