bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–04–06
nine papers selected by
Grigor Varuzhanyan, UCLA
  1. MicroRNA-335 inhibits invasion and metastasis of prostate cancer by inhibiting glutamine metabolism pathway.
  2. Oxidative stress as a catalyst in prostate cancer progression: unraveling molecular mechanisms and exploring therapeutic interventions.
  3. Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies.
  4. 20(S)-ginsenoside Rg3 induced the necroptosis of prostate cancer cells via ROS overproduction.
  5. Resilience and vulnerabilities of tumor cells under purine shortage stress.
  6. Exploring the roles of ncRNAs in prostate cancer via the PI3K/AKT/mTOR signaling pathway.
  7. Artesunate enhances the efficacy of Enzalutamide in advanced prostate cancer.
  8. Insulin resistance: a paradoxical protector against low-grade prostate cancer? Findings from the REDUCE trial.
  9. Corrigendum: Astragalus-Scorpion drug pair inhibits the development of prostate cancer by regulating GDPD4-2/PI3K/AKT/mTOR pathway and autophagy.
  1. J Pharmacol Exp Ther. 2025 Mar;pii: S0022-3565(24)42179-4. [Epub ahead of print]392(3): 100530
    MicroRNA-335 inhibits invasion and metastasis of prostate cancer by inhibiting glutamine metabolism pathway.
    Ziqi Chen, Hekang Ding, Yunlong Zhu, Shuai Sun, Zhenyu Song, Li Zhang, Chaozhao Liang, Lingfan Xu.
      MicroRNAs play a crucial role in regulating tumor progression and invasion. Nevertheless, the expression of miRNA-335 in prostate cancer (PCa) and its clinical significance remain unelucidated. Here, we report that miRNA-335 functions as a tumor suppressor by regulating expression of glutaminase 1 (GLS1), a key enzyme of glutamine metabolism pathway, in PCa. In this study, we show that the expression of miRNA-335 is downregulated in PCa tissues. The level of miRNA-335 is even lower in highly invasive PCa cell lines. Furthermore, enhancing the expression of miRNA-335 inhibits PCa cell migration and invasion in vitro. Additionally, we identify GLS1 as the downstream effector, governed by miRNA-335 via 3'-untranslated region, and the direct regulation is verified by dual luciferase reporter assay. MiRNA-335 interrupts glutamine catabolism by inhibiting GLS1 enzymatic activity. Overexpression of miRNA-335 markedly suppresses tumor growth of PCa in vivo. To sum up, our results indicate that miRNA-335 acts as a tumor suppressor and has an important role in restraining the metastasis of PCa cells by targeting GLS1. These discoveries indicate that miRNA-335 could serve as a new prospective therapeutic target for PCa. SIGNIFICANCE STATEMENT: miRNA-335, a metabolism-related microRNA, is a potential therapeutic target for prostate cancer by interfering with glutaminase 1 activity.
    Keywords:  Glutaminase 1; Glutamine; MicroRNA; MicroRNA-335; Prostate cancer; miRNA-335
    DOI:  https://doi.org/10.1016/j.jpet.2024.100530
  2. Discov Oncol. 2025 Apr 03. 16(1): 457
    Oxidative stress as a catalyst in prostate cancer progression: unraveling molecular mechanisms and exploring therapeutic interventions.
    Yawen Song, Zheng Hou, Longting Zhu, Yan Chen, Jingyu Li.
      Prostate cancer is the second most common malignancy among men worldwide, with its incidence and mortality rates steadily increasing. Although androgen deprivation therapy (ADT) combined with androgen receptor inhibitors has shown significant efficacy in treating prostate cancer, resistance to treatment remains a major challenge, particularly in patients with metastatic prostate cancer. Reactive oxygen species (ROS), a class of highly reactive molecules, can induce oxidative stress within cells, thereby affecting cellular survival and function. In cancer cells, elevated ROS levels not only promote proliferation and invasion but also contribute to the malignancy of tumors by modulating the tumor microenvironment, enhancing angiogenesis, and facilitating extracellular matrix remodeling. This review systematically explores the pathways of ROS generation in prostate cancer, their interaction with the androgen receptor signaling pathway, and the role of external factors such as obesity and aging in promoting ROS production. The findings highlight that ROS drive prostate cancer progression through multiple mechanisms, including altering the tumor microenvironment, activating the unfolded protein response (UPR), and regulating miRNA expression. By providing a comprehensive analysis of ROS-mediated mechanisms in prostate cancer, this review offers new insights into the development of targeted antioxidant therapeutic strategies.
    Keywords:  Antioxidants; Prostate cancer; ROS
    DOI:  https://doi.org/10.1007/s12672-025-02245-4
  3. Nat Commun. 2025 Apr 03. 16(1): 3189
    Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies.
    Wei Ou, Xin-Xin Zhang, Bin Li, Ying Tuo, Ren-Xuan Lin, Peng-Fei Liu, Jian-Ping Guo, Hio-Cheng Un, Ming-Hao Li, Jia-Hao Lei, Xiao-Jing Gao, Fu-Fu Zheng, Ling-Wu Chen, Ling-Li Long, Zong-Ren Wang.
      Localized prostate cancer (PCa) is highly variable in their response to therapies. Although a fraction of this heterogeneity can be explained by clinical factors or genomic and transcriptomic profiling, the proteomic-based profiling of aggressive PCa remains poorly understood. Here, we profiled the genome, transcriptome, proteome and phosphoproteome of 145 cases of localized PCa in Chinese patients. Proteome-based stratification of localized PCa revealed three subtypes with distinct molecular features: immune subgroup, arachidonic acid metabolic subgroup and sialic acid metabolic subgroup with highest biochemical recurrence (BCR) rates. Further, we nominated NANS protein, a key enzyme in sialic acid synthesis as a potential prognostic biomarker for aggressive PCa and validated in two independent cohorts. Finally, taking advantage of cell-derived orthotopic transplanted mouse models, single-cell RNA sequencing (scRNA-seq) and immunofluorescence analysis, we revealed that targeting NANS can reverse the immunosuppressive microenvironment through restricting the sialoglycan-sialic acid-recognizing immunoglobulin superfamily lectin (Siglec) axis, thereby inhibiting tumor growth of PCa. In sum, we integrate multi-omic data to refine molecular subtyping of localized PCa, and identify NANS as a potential prognostic biomarker and therapeutic option for aggressive PCa.
    DOI:  https://doi.org/10.1038/s41467-025-58569-w
  4. Neoplasma. 2025 Mar 28. pii: 240925N402. [Epub ahead of print]
    20(S)-ginsenoside Rg3 induced the necroptosis of prostate cancer cells via ROS overproduction.
    Yanfei Peng, Yaping Guo, Shuwu Zhao, Hao Yan, Zheng Hao, Fang Zheng, Zhaiyi Zhang, Lin Miao, Li-Kang Sun, Muriel Cuendet.
      Necroptosis is a programmed form of necrosis and compounds inducing necroptosis may contribute to cancer treatment. 20(S)-ginsenoside Rg3 is a natural compound extracted from ginseng, which exhibited a broad-spectrum of antitumor activity. In the present study, the potential role of 20(S)-ginsenoside Rg3 in inducing necroptosis in prostate cancer cells was evaluated. 20(S)-ginsenoside Rg3 inhibited the proliferation of prostate cancer cells and upregulated the expression of necroptotic proteins such as receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3, and their downstream mixed lineage kinase domain-like protein (MLKL). Pretreatment with the selective RIPK1 inhibitor necrostatin-1 (Nec-1) partially reversed the inhibitory effect of 20(S)-ginsenoside Rg3 on prostate cancer cell proliferation. 20(S)-ginsenoside Rg3 led to the accumulation of reactive oxygen species (ROS) and the regulation of autophagy in cancer cells. Scavenging ROS with N-acetyl-L-cysteine (NAC) antagonized the regulatory effects of 20(S)-ginsenoside Rg3 on cell autophagy and necroptotic proteins expression. Moreover, 20(S)-ginsenoside Rg3 exhibited an antitumor effect in a prostate cancer xenograft mouse model in which it upregulated the expression of RIPK1, RIPK3, MLKL and led to a decrease in tumor weight, as well as an increase in necrotic areas in tumor tissue. In conclusion, our study showed that 20(S)-ginsenoside Rg3 might induce necroptosis in prostate cancer in vitro and in vivo via the ROS/autophagy signaling pathway.
    DOI:  https://doi.org/10.4149/neo_2025_240925N402
  5. bioRxiv. 2025 Mar 20. pii: 2025.03.19.644180. [Epub ahead of print]
    Resilience and vulnerabilities of tumor cells under purine shortage stress.
    Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel J George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang.
      Purine metabolism is a promising therapeutic target in cancer; however how cancer cells respond to purine shortage,particularly their adaptation and vulnerabilities, remains unclear. Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated these responses in prostate, lung and glioma cancer models. We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multi-protein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit Methylthioadenosine Phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer (PCa) models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity. Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.
    DOI:  https://doi.org/10.1101/2025.03.19.644180
  6. Front Immunol. 2025 ;16 1525741
    Exploring the roles of ncRNAs in prostate cancer via the PI3K/AKT/mTOR signaling pathway.
    Rongwang Guo, Liji Shi, Yonghui Chen, Canling Lin, Weihua Yin.
      Although various treatment options are available for prostate cancer (PCa), including androgen deprivation therapy (ADT) and chemotherapy, these approaches have not achieved the desired results clinically, especially in the treatment of advanced chemotherapy-resistant PCa. The PI3K/AKT/mTOR (PAM) signaling pathway is a classical pathway that is aberrantly activated in cancer cells and promotes the tumorigenesis, metastasis, resistance to castration therapy, chemoresistance, and recurrence of PCa. Noncoding RNAs (ncRNAs) are a class of RNAs that do not encode proteins. However, some ncRNAs have recently been shown to be differentially expressed in tumor tissues compared with noncancerous tissues and play important roles at the transcription and posttranscription levels. Among the types of ncRNAs, long noncoding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), and Piwi-interacting RNAs (piRNAs) can participate in the PAM pathway to regulate PCa growth, metastasis, angiogenesis, and tumor stemness. Therefore, ncRNA therapy that targets the PAM signaling pathway is expected to be a novel and effective approach for treating PCa. In this paper, we summarize the types of ncRNAs that are associated with the PAM pathway in PCa cells as well as the functions and clinical roles of these ncRNAs in PCa. We hope to provide novel and effective strategies for the clinical diagnosis and treatment of PCa.
    Keywords:  PI3K/AKT/mTOR; metastasis; ncRNA; prostate cancer; tumor growth
    DOI:  https://doi.org/10.3389/fimmu.2025.1525741
  7. J Biol Chem. 2025 Mar 26. pii: S0021-9258(25)00307-2. [Epub ahead of print] 108458
    Artesunate enhances the efficacy of Enzalutamide in advanced prostate cancer.
    Xinyi Wang, Jinghui Liu, Fengyi Mao, Yifan Kong, Qiongsi Zhang, Chaohao Li, Daheng He, Chi Wang, Yanquan Zhang, Ruixin Wang, Sally R Ellingson, Qiou Wei, Zhiguo Li, Xiaoqi Liu.
      Prostate cancer (PCa) is one of the leading causes of death among men worldwide. Treatments targeting the androgen receptor (AR) pathway remain the standard therapy for PCa patients. Enzalutamide (ENZ), a second-generation AR inhibitor, was developed to treat castration-resistant prostate cancer (CRPC). However, while patients initially respond to ENZ, drug resistance typically develops within a few months. Artesunate (ART), a semi-synthetic derivative of the Artemisinin plant, is approved for anti-malaria treatment. In this study, we conducted an FDA-approved drug screening and identified Artesunate as a potential candidate for overcoming ENZ resistance in prostate cancer (ENZ-R PCa). Mechanistically, ART induces the degradation of c-Myc, enhancing the efficacy of ENZ. Additionally, patient dataset analysis revealed that c-Myc plays a significant role in developing ENZ resistance. To summarize, these findings suggest a novel therapeutic strategy for ENZ-resistant prostate cancer.
    Keywords:  Artesunate; c-Myc; enzalutamide resistance; prostate cancer
    DOI:  https://doi.org/10.1016/j.jbc.2025.108458
  8. Postgrad Med J. 2025 Apr 03. pii: qgaf047. [Epub ahead of print]
    Insulin resistance: a paradoxical protector against low-grade prostate cancer? Findings from the REDUCE trial.
    Rupak Desai, Akhil Jain.
      
    Keywords:  cancer; oncology; prostate cancer; urology
    DOI:  https://doi.org/10.1093/postmj/qgaf047
  9. Front Pharmacol. 2025 ;16 1417603
    Corrigendum: Astragalus-Scorpion drug pair inhibits the development of prostate cancer by regulating GDPD4-2/PI3K/AKT/mTOR pathway and autophagy.
    Xujun You, Yongrong Wu, Qixin Li, Wen Sheng, Qing Zhou, Wei Fu.
      [This corrects the article DOI: 10.3389/fphar.2022.895696.].
    Keywords:  Astragaloside IV; Astragalus–Scorpio; PI3K/AKT; autophagy; polypeptide extract from scorpion venom; prostate cancer
    DOI:  https://doi.org/10.3389/fphar.2025.1417603
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