bims-meproc 2025-04-27 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–04–27
sixteen papers selected by
Grigor Varuzhanyan, UCLA

Lipolysis-stimulated lipoprotein receptor is involved in fatty acid binding protein 4-mediated prostate cancer cell growth in bone.
Valosin-Containing Protein (VCP/p97) Mediates Neuroendocrine Differentiation in Prostate Cancer Cells Through Pim1 Signaling Inducing Autophagy.
BCAT2 binding to PCBP1 regulates the PI3K/AKT signaling pathway to inhibit autophagy-related apoptosis and ferroptosis in prostate cancer.
Nanoparticles with curcumin and piperine modulate steroid biosynthesis in prostate cancer.
Urolithins: Emerging natural compound targeting castration-resistant prostate cancer (CRPC).
Secreted spermidine synthase reveals a paracrine role for PGC1α-induced growth suppression in prostate cancer.
Acute BRCAness induction and AR pathway blockage through CDK12/7/9 degradation enhances PARP inhibitor sensitivity in prostate cancer.
SMC4 Promotes Prostate Cancer Cell Proliferation and Metastasis via the Rheb/mTOR Pathway.
Prostate cancer exploits BRD9-driven metabolic reprogramming to shape the aggressive phenotype.
An expanded metabolic pathway for androgen production by commensal bacteria.
Mendelian randomization analysis reveals potential causal relationships between serum lipid metabolites and prostate cancer risk.
PSMA-Targeted Nanoparticles with PI3K/mTOR Dual Inhibitor Downregulate P-Glycoprotein and Inactivate Myeloid-Derived Suppressor Cells for Enhanced Chemotherapy and Immunotherapy in Prostate Cancer.
p-AKT protein expression predicts response to AKT inhibitor combined with docetaxel therapy in adenocarcinoma and neuroendocrine prostate cancer.
Asymmetric cell division of ALDH1-positive cancer stem cells generates glycolytic metabolically diverse cell populations.
Stachydrine hydrochloride induces cell senescence and ferroptosis of castration-resistant prostate cancer.
Gut microbiota and prostate cancer: an analysis of bacterial communities across various clinical scenarios.

J Med Invest. 2025 ;72(1.2): 34-41

Lipolysis-stimulated lipoprotein receptor is involved in fatty acid binding protein 4-mediated prostate cancer cell growth in bone.

Tetsuyuki Takahashi, Takaaki Tsunematsu, Hisanori Uehara.

  Obesity-induced excess adipokine production is associated with malignancy and mortality in prostate cancer. We previously showed that fatty acid binding protein 4 (FABP4), a major adipokine of mature adipocytes, promotes the progression of prostate cancer cell growth and invasion. In this report, we present lipolysis-stimulated lipoprotein receptor (LSR) as a newly identified binding partner for FABP4. Their binding induced Akt phosphorylation, whereas LSR knockdown (KD) failed to phosphorylate Akt. Intraosseous injection of LSR-KD prostate cancer cells showed smaller areas of intraosseous tumor, lower Ki-67 labeling indices, and lower numbers of phospho-Akt-positive cancer cells compared with control prostate cancer cells. Moreover, the contact coculture of prostate cancer cells with bone marrow stromal cells (BMSCs) promoted FABP4 secretion by BMSCs. Our findings indicated that FABP4-mediated prostate cancer cell progression was regulated by cellular signaling via FABP4-LSR binding in the bone microenvironment. J. Med. Invest. 72 : 34-41, February, 2025.

Keywords:  Lipolysis-stimulated lipoprotein receptor; bone microenvironment; fatty acid binding protein 4; prostate cancer

DOI:  https://doi.org/10.2152/jmi.72.34
Prostate. 2025 Apr 23.

Valosin-Containing Protein (VCP/p97) Mediates Neuroendocrine Differentiation in Prostate Cancer Cells Through Pim1 Signaling Inducing Autophagy.

K K Sruthi, Ramesh Ummanni.

   BACKGROUND: Neuroendocrine Prostate Cancer (NEPC) is an aggressive type of androgen-independent prostate cancer (AIPC) associated with resistance to treatment. Valosin-containing protein (VCP/p97) has been found to be overexpressed in prostate cancer (PCa) cells undergoing neuroendocrine differentiation (NED) in response to interleukin-6 (IL-6). This study explores the molecular mechanisms through which VCP/p97 contributes to the progression of NEPC.
METHODS: To investigate the role of VCP/p97 in the NED of PCa, we overexpressed the VCP/p97 in PCa cells. The molecular mechanisms underlying VCP/p97 induced NED were assessed by using western blot analysis and RT-PCR. Morphological changes were analyzed by using both bright field and confocal microscope. Lysotracker staining was performed to identify autophagy in VCP positive PCa cells.
RESULTS: In the present study, we found that VCP/p97 expression was notably higher in neuroendocrine (NE) cells NCI-H660 and PC3 than in other PCa cells. IL-6 treatment led to significant VCP/p97 overexpression in LNCaP and VCaP cells, with a marked increase in NE markers NSE and CHR-A. Inhibition of VCP/p97 using NMS-873 attenuated NED features, suggesting that VCP/p97 is required for NED progression. Moreover, VCP's role in NED is linked to its regulation via Pim1 in differentiating cells. Exogenous expression of VCP/p97 enhanced Pim1 and c-Myc expression, which were diminished upon VCP/p97 inhibition which is corroborated by reduced NED markers. Pim1 inhibition using AZD1208 and c-Myc knockdown further supported Pim1's involvement in VCP mediated NED. To promote NED, VCP/p97 regulated autophagy, as evidenced by increased LC3B and decreased SQSTM1/p62 levels upon VCP overexpression. Inhibition of VCP/p97 or autophagy disrupted NED and autophagic flux, arresting NED of LNCaP cells. Lysotracker staining and autophagic flux assays confirmed VCP's role in enhancing lysosomal-mediated autophagy and autophagolysosome formation. Furthermore, we show that AMPK activation, via LKB1 is essential for VCP/p97 mediated NED and autophagy.
CONCLUSION: VCP drives NED in PCa cells through a complex interplay involving the Pim1 axis and autophagy pathways. These findings highlight the potential of targeting VCP/p97 and its associated mechanisms as therapeutic strategies to inhibit NED progression.

Keywords:  IL‐6; LC3A/B; LNCaP cells; NE markers; Pim‐1; VCaP cells; autophagy

DOI:  https://doi.org/10.1002/pros.24900
Cell Death Dis. 2025 Apr 24. 16(1): 337

BCAT2 binding to PCBP1 regulates the PI3K/AKT signaling pathway to inhibit autophagy-related apoptosis and ferroptosis in prostate cancer.

Wangli Mei, Mengyu Wei, Chaozhi Tang, Weiyi Li, Bowen Ye, Shiyong Xin, Weiguo Ma, Lin Ye.

Prostate cancer (PCa) has emerged as a predominant cause of cancer-related mortality among men globally. The mechanisms of branched-chain amino acids (BCAAs) contributing to the development of PCa remain inadequately elucidated. The objective of this study was to examine the involvement of BCAAs and BCAT2 in tumorigenesis. BCAAs exhibited elevated expression levels in PCa tissues and cells. Among the critical enzymes involved in the BCAA metabolic pathway, only BCAT2 demonstrated significant expression in PCa and was closely associated with tumor progression and patient prognosis. RNA sequencing along with related functional experiments indicated that BCAT2 can inhibit autophagy, autophagy-related apoptosis, and ferroptosis in PCa. Furthermore, the results of co-immunoprecipitation, mass spectrometry, and other methodologies established that PCBP1, as a downstream protein interacting with BCAT2, co-regulates the PI3K/AKT pathway, thereby influencing progression of PCa. Moreover, BCAT2 interacted with PCBP1 at Leucine 239 to collaboratively regulate the PI3K/AKT signaling pathway, which is crucial for the initiation and progression of PCa. Targeting BCAT2 may represent a promising therapeutic strategy to prevent proliferation of PCa.

DOI: https://doi.org/10.1038/s41419-025-07559-3
Sci Rep. 2025 Apr 19. 15(1): 13613

Nanoparticles with curcumin and piperine modulate steroid biosynthesis in prostate cancer.

Jibira Yakubu, Evangelos Natsaridis, Therina du Toit, Isabel Sousa Barata, Oya Tagit, Amit V Pandey.

  Endogenous androgens are pivotal in the development and progression of prostate cancer (PC). We investigated nanoparticle formulations of curcumin and piperine in modulating steroidogenesis within PC cells. Using multiple PC cell lines (LNCaP, VCaP, DU145 and PC3) we studied the effects of curcumin, piperine, and their nanoparticle formulations-curcumin nanoparticles, piperine nanoparticles, and curcumin-piperine nanoparticles (CPN)-on cell viability, migration, and steroid biosynthesis. Curcumin and its nanoparticle formulations significantly reduced cell viability in PC cells, with curcumin-piperine nanoparticles showing the highest efficacy. These treatments also inhibited cell migration, with CPN exhibiting the most pronounced effect. In assays for steroid biosynthesis, curcumin, and its nanoparticle formulations, as well as piperine and its nanoparticles, selectively inhibited 17α-hydroxylase and 17,20-lyase activities of cytochrome P450 17A1 (CYP17A1). Abiraterone, a CYP17A1 inhibitor, displayed a broader inhibition of steroid metabolism including cytochrome P450 21-hydroxylase activity, whereas curcumin and piperine provided a more targeted inhibition profile. Analysis of steroid metabolites by liquid chromatography-mass spectrometry revealed that CPN caused significant reduction of androstenedione and cortisol, suggesting potential synergistic effects. In conclusion, nanoformulations co-loaded with curcumin and piperine offer an effective approach to targeting steroidogenesis and could be promising candidates for therapies aimed at managing androgen-dependent PC.

Keywords:  Androgen synthesis; CYP17A1; Curcumin nanoparticles; Nanoparticle formulations; Prostate cancer; Steroidogenesis

DOI:  https://doi.org/10.1038/s41598-025-98102-z
Biomed Pharmacother. 2025 Apr 19. pii: S0753-3322(25)00252-5. [Epub ahead of print]187 118058

Urolithins: Emerging natural compound targeting castration-resistant prostate cancer (CRPC).

Ajit Kumar Navin, Chalikkaran Thilakan Rejani, Balaji Chandrasekaran, Ashish Tyagi.

Castration-resistant prostate cancer (CRPC) presents a significant challenge due to its resistance to conventional androgen deprivation therapies. Urolithins, bioactive metabolites derived from ellagitannins, have recently emerged as promising therapeutic agents for CRPC. Urolithins not only inhibit androgen receptor (AR) signaling, a crucial factor in the progression of CRPC, but also play a key role in regulating oxidative stress by their antioxidant properties, thereby inhibiting increased reactive oxygen species, a common feature of the aggressive nature of CRPC. Research has shown that urolithins induce apoptosis and diminish pro-survival signaling, leading to tumor inhibition. This review delves into the intricate mechanisms through which urolithins exert their therapeutic effects, focusing on both AR-dependent and AR-independent pathways. It also explores the exciting potential of combining urolithins with androgen ablation therapy, opening new avenues for CRPC treatment.

DOI: https://doi.org/10.1016/j.biopha.2025.118058
Cell Death Dis. 2025 Apr 23. 16(1): 330

Secreted spermidine synthase reveals a paracrine role for PGC1α-induced growth suppression in prostate cancer.

Ariane Schaub-Clerigué, Ivana Hermanova, Ainara Pintor-Rial, Mariia Sydorenko, Lorea Valcarcel-Jimenez, Alice Macchia, Benoit Lectez, Saioa Garcia-Longarte, Maider Fagoaga-Eugui, Ianire Astobiza, Natalia Martín-Martín, Amaia Zabala-Letona, Mikel Pujana-Vaquerizo, Félix Royo, Mikel Azkargorta, Edurne Berra, James D Sutherland, Héctor Peinado, Juan Manuel Falcón-Perez, Félix Elortza, Arkaitz Carracedo, Verónica Torrano.

Prostate cancer is the fifth cause of death by cancer worldwide, second in incidence in the male population. The definition of the molecular basis of its development and the oncogenic signals driving lethality continue to be important objectives in prostate cancer research. Prior work from others and us has demonstrated that loss of PGC1α expression results in a metabolic, signaling and transcriptional reprogramming that supports the development of metastatic disease. However, we do not fully understand the spectrum of tumor suppressive effects regulated by this co-regulator. Here we show that PGC1α governs non-cell autonomous paracrine tumor suppression in prostate cancer. A systematic analysis of the transcriptional landscapes associated to PGC1α loss of expression revealed that PGC1α alters the expression of genes encoding for secreted proteins. Cell secretome studies corroborated that PGC1α-dependent ERRα regulation in prostate cancer cells suppresses the growth of tumor cells exposed to their conditioned media, independently of androgen receptor status. The integration of in vitro and in vivo secretomics data and genetic perturbation assays revealed spermidine synthase as a transcriptional target of PGC1α and mediator of the paracrine metabolic growth suppressive effect. Moreover, the activity of the regulatory axis PGC1α-ERRα-SRM was reflected in patients and had prognostic value. Altogether, this work provides unprecedented evidence of the non-cell autonomous suppressive role of PGC1α, which broadens the view of this co-regulator as a multifactorial tumor suppressor in prostate cancer.

DOI: https://doi.org/10.1038/s41419-025-07639-4
Sci Adv. 2025 Apr 25. 11(17): eadu0847

Acute BRCAness induction and AR pathway blockage through CDK12/7/9 degradation enhances PARP inhibitor sensitivity in prostate cancer.

Fu Gui, Baishan Jiang, Jie Jiang, Zhixiang He, Takuya Tsujino, Tomoaki Takai, Seiji Arai, Celine Pana, Jens Köllermann, Gary Andrew Bradshaw, Robyn Eisert, Marian Kalocsay, Anne Fassl, Steven P Balk, Adam S Kibel, Li Jia.

Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APPIs) remains ongoing challenges. Here, we present BSJ-5-63, a proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multipronged approach to CRPC therapy. BSJ-5-63 degrades CDK12, diminishing BRCA1 and BRCA2 expression and inducing a sustained "BRCAness" state. This sensitizes cancer cells to PARP inhibitors (PARPis) regardless of their homologous recombination repair (HRR) status. Furthermore, CDK7 and CDK9 degradation attenuates AR signaling, enhancing its therapeutic efficacy. Preclinical studies, including both in vitro and in vivo CRPC models, demonstrate that BSJ-5-63 exerts potent antitumor activity in both AR-positive and AR-negative setting. This study introduces BSJ-5-63 as a promising therapeutic agent that addresses both DNA repair and AR signaling mechanisms, with potential benefits for a board patient population.

DOI: https://doi.org/10.1126/sciadv.adu0847
Adv Sci (Weinh). 2025 Apr 25. e2500369

SMC4 Promotes Prostate Cancer Cell Proliferation and Metastasis via the Rheb/mTOR Pathway.

Wei Zhang, Siyuan Qin, Xiaokang Li, Ming Chang, Tianzi Wei, Xin Huang, Haibo Tong, Xia Guo, Yi Lu, Jian Zhang.

  Structural maintenance of chromosome protein 4 (SMC4), is a key structural component of mitotic chromosomes. While existing evidence indicates a plausible link between SMC4 and oncogenic manifestations, its precise role in the trajectory of prostate cancer remains ambiguous. The Cancer Genome Atlas (TCGA) database analysis reveals that aberrant expression of SMC4 exhibits a robust prognostic association with metastatic progression. To investigate the function of SMC4, the SMC4 gene is knocked down in RM1-LM cells, a highly metastatic cell clone is developed, using the CRISPR/Cas9 system. The results show that SMC4 knockdown significantly diminished cell proliferation and migration in vitro. Furthermore, in a murine model, RM1-LM cells display higher lung metastasis capabilities than SMC4 knockdown cells. SMC4 knockdown inhibited the activation of mTOR and downregulated the expression of Rheb. KEGG enrichment analyses of the RNA-seq results reveal that cancer signaling pathways and metabolic pathways are enriched. The SMC4 interactome is uncovered through IP-MS and indicates that SMC4 interacts with GLUT1, encoded by Slc2a1. Glycolytic rate assay illustrates that knocking down SMC4 inhibits the cell glycolysis rate and ATP production. Collectively, the data suggests that the interaction between SMC4 and GLUT1, as confirmed by co-IP, promotes prostate cancer cell metastasis through the Rheb/mTOR pathway.

Keywords:  GLUT1; SMC4; metastasis; prostate cancer

DOI:  https://doi.org/10.1002/advs.202500369
Cell Death Dis. 2025 Apr 22. 16(1): 326

Prostate cancer exploits BRD9-driven metabolic reprogramming to shape the aggressive phenotype.

Ye Lv, Xinkai Mo, Ruojia Zhang, Yu Peng, Tingting Feng, Yuang Zhang, Guanhua Song, Luna Ge, Yu Liu, Guiwen Yang, Lin Wang.

The aggressive phenotype of prostate cancer (PCa) requires adaptation to androgen deprivation (AD) to progress into castration-resistant PCa (CRPC), including adaptation to AD-induced oxidative stress. However, our understanding of the oncogenes that maintain the redox balance during CRPC progression is limited. Here, we identified Bromodomain-containing protein 9 (BRD9) as a metabolic checkpoint for reprogramming cell metabolism to support tumor growth and impart a castration-resistant phenotype under metabolic and oxidative stress. Following oxidation, BRD9 recruited the nuclear transcription factor-Y A-subunit (NFYA) to induce glycogen phosphorylase L (PYGL) expression, which directed glucose utilization through the pentose phosphate pathway, generating NADPH, and promoting clearance of reactive oxygen species (ROS), thus maintaining redox balance. By disturbing redox homeostasis, BRD9 inhibition exerted oxidative pressure on PCa cells, sensitizing them to radiotherapy. This work identified BRD9 as a novel component in antioxidant reprogramming and indicates BRD9 targeting as a promising treatment strategy for PCa therapy.

DOI: https://doi.org/10.1038/s41419-025-07561-9
Nat Microbiol. 2025 Apr 21.

An expanded metabolic pathway for androgen production by commensal bacteria.

Taojun Wang, Saeed Ahmad, Angélica Cruz-Lebrón, Sarah E Ernst, Kelly Yovani Olivos Caicedo, Yoon Jeong, Briawna Binion, Pauline Mbuvi, Debapriya Dutta, Francelys V Fernandez-Materan, Adam M Breister, Elizabeth Tang, Jae Won Lee, Jason D Kang, Spencer C Harris, Shigeo Ikegawa, H Rex Gaskins, John W Erdman, Glen Yang, Isaac Cann, Steven L Daniel, Phillip B Hylemon, Karthik Anantharaman, Rafael C Bernardi, João M P Alves, Karen S Sfanos, Joseph Irudayaraj, Jason M Ridlon.

Commensal bacteria have been implicated in the modulation of steroid hormones, including circulating androgen levels in the host. However, the microbial genetic pathways involved in androgen production have not been fully characterized. Here we identify a microbial gene encoding an enzyme that catalyses the conversion of androstenedione to epitestosterone in the gut microbiome member Clostridium scindens and named this gene desF. We demonstrate that epitestosterone impacts androgen receptor-dependent prostate cancer cell proliferation in vitro. We also demonstrate that stool desF levels are elevated in patients with prostate cancer who are unresponsive to abiraterone/prednisone therapy. Bacterial isolates from urine or prostatectomy tissue produced androgens, and 17β-hydroxysteroid dehydrogenase activity encoded by the desG gene was detected in strains of the urinary tract bacterium Propionimicrobium lymphophilum. Furthermore, we demonstrate that urinary androgen-producing bacterial strains can promote prostate cancer cell growth through metabolism of cortisol and prednisone. Abiraterone, which targets host desmolase (CYP17A1), a rate-limiting enzyme in adrenal steroidogenesis, does not inhibit bacterial desmolase (DesAB), whereas the conversion of prednisone to androgens by DesAB, DesF and DesG drives androgen-receptor-dependent prostate cancer cell line proliferation in vitro. Our results are a significant advance in steroid microbiology and highlight a potentially important role for gut and urinary tract bacteria in host endocrine function and drug metabolism.

DOI: https://doi.org/10.1038/s41564-025-01979-9
Discov Oncol. 2025 Apr 24. 16(1): 602

Mendelian randomization analysis reveals potential causal relationships between serum lipid metabolites and prostate cancer risk.

Chuanmin Guo, Lejun Wu, Lintang Xu.

   BACKGROUND: Prostate cancer is a common malignancy in men, with its pathogenesis not yet fully elucidated. Recent years have seen increased attention on the relationship between lipid metabolism abnormalities and prostate cancer risk. This study aims to explore the potential causal relationships between serum lipid metabolites and prostate cancer risk using Mendelian randomization methods.
METHODS: This study employed Mendelian randomization methods to analyze the relationship between various serum lipid metabolites (including phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, etc.) and prostate cancer risk using GWAS datasets from the UK Biobank. The research analyzed data from 182,625 participants of European descent, including 9132 prostate cancer cases and 173,493 controls. Multiple statistical methods were used for analysis, including inverse variance weighted method, MR Egger regression method, and weighted median approach. Results were presented through forest plots, funnel plots, and scatter plots.
RESULTS: The study found that most serum lipid metabolites likely do not have strong causal relationships with prostate cancer risk. However, some metabolites showed weak associations: phosphatidylethanolamine (16:0_20:4) levels demonstrated a weak negative correlation with prostate cancer risk, while phosphatidylinositol (18:0_20:4) levels showed a weak positive correlation. The consistency of results across most analytical methods enhanced the reliability of these findings.
CONCLUSION: This study provides important insights into the complex relationship between serum lipid metabolites and prostate cancer risk. Although most lipid metabolites may not be strong determinants of prostate cancer risk, certain specific metabolites may have weak associations.

Keywords:  Causal relationship; Lipid metabolism; Mendelian randomization; Phosphatidylinositol; Prostate cancer

DOI:  https://doi.org/10.1007/s12672-025-02388-4
Adv Mater. 2025 Apr 21. e2415322

PSMA-Targeted Nanoparticles with PI3K/mTOR Dual Inhibitor Downregulate P-Glycoprotein and Inactivate Myeloid-Derived Suppressor Cells for Enhanced Chemotherapy and Immunotherapy in Prostate Cancer.

Lu Yin, Feiya Yang, Wenkuan Wang, Lingpu Zhang, Zheng Cao, Haoyuan Shi, Kehao Pan, Liyuan Wu, Haihua Xiao, Nianzeng Xing.

  Acquired drug resistance and the immunosuppressive tumor microenvironment significantly limit the efficacy of chemotherapy and immunotherapy in advanced prostate cancer. Blocking the PI3K/mTOR signaling pathway has been recently proved as a new strategy to improve sensitivity to chemotherapy and immunotherapy. Herein, glutathione (GSH)-sensitive nanoparticles (PSMA-NP/BEZ) are developed that can target prostate-specific membrane antigen (PSMA), loaded with PI3K/mTOR dual inhibitor prodrug BEZ235. BEZ235 can be released from PSMA-NP/BEZ in response to elevated GSH levels in prostate cancer tissues, inhibiting the PI3K/AKT/mTOR pathway and impairing downstream cellular functions such as cell proliferation, DNA repair, and protein synthesis. When combined with paclitaxel, PSMA-NP/BEZ could reduce drug efflux by downregulating P-glycoprotein expression in cancer cells, thus enhancing the sensitivity to chemotherapy. Furthermore, PSMA-NP/BEZ could impair the immunosuppressive functions of myeloid-derived suppressor cells and reshape the "cold" immune microenvironment in prostate cancer, enhancing immunotherapeutic efficacy and including long-term immune memory against tumor recurrence. PSMA-NP/BEZ serves a safe and promising strategy to improve the efficacy of chemotherapy and immunotherapy in advanced prostate cancer.

Keywords:  PI3K/mTOR inhibitor; P‐glycoprotein; drug resistance; myeloid‐derived suppressor cells; nanoparticles; prostate‐specific membrane antigen

DOI:  https://doi.org/10.1002/adma.202415322
Clin Cancer Res. 2025 Apr 25.

p-AKT protein expression predicts response to AKT inhibitor combined with docetaxel therapy in adenocarcinoma and neuroendocrine prostate cancer.

Hipacia Werneck Gomes, Natalie L Lister, Shivakumar Keerthikumar, Birunthi Niranjan, Michelle G Richards, Andrew Ryan, Edmond M Kwan, Gail P Risbridger, Renea A Taylor.

PURPOSE: AKT inhibitors, such as capivasertib, have shown activity in specific patients with metastatic castration-resistant prostate cancer when combined with docetaxel, although none have been approved. While PTEN loss is often linked to AKT pathway activation and response to AKT inhibitors, clinical trials show no consistent association. This study uses patient-tumor models to identify biomarkers associated with an effective response to AKT inhibitor plus docetaxel.
EXPERIMENTAL DESIGN: Targeted DNA sequencing and immunostaining for PTEN and p-AKT(Ser473) was assessed in 39 prostate cancer patient-derived xenografts (PDXs), including adenocarcinoma and neuroendocrine phenotypes. Matching PDX-derived organoids were used to evaluate the functional effects of capivasertib and docetaxel on in vitro tumor growth.
RESULTS: p-AKT protein expression varied widely across PDX models and showed no correlation with PTEN/PI3K/AKT mutations or PTEN protein levels. Neuroendocrine tumors displayed higher p-AKT expression than adenocarcinomas. Knockdown of AKT1 in neuroendocrine organoids increased sensitivity to docetaxel, while AKT1 overexpression decreased it. In three out of seven organoids tested, the combination of capivasertib and docetaxel produced a synergistic effect, resulting in greater growth inhibition than either agent alone. These responsive organoids exhibited a neuroendocrine phenotype and high p-AKT expression, consistent with a predictive response.
CONCLUSIONS: Our preclinical findings indicate that p-AKT protein expression, rather than PTEN, may be a more reliable predictor of response to AKT inhibition combined with docetaxel. Using p-AKT as a parameter, we uncovered the efficacy of this combination in neuroendocrine prostate cancer, highlighting the potential to refine patient selection criteria for future clinical trials.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3848
Sci Rep. 2025 Apr 22. 15(1): 13932

Asymmetric cell division of ALDH1-positive cancer stem cells generates glycolytic metabolically diverse cell populations.

Shoma Tamori, Chika Matsuda, Takahiro Kasai, Shigeo Ohno, Kazunori Sasaki, Kazunori Akimoto.

Metabolic heterogeneity in various cancer cells within a tumor causes resistance to medical therapies and promotes tumor recurrence and metastasis. However, the mechanisms by which tumors acquire metabolic heterogeneity are poorly understood. Here, we revealed that PKCλ-dependent asymmetric division of ALDH1-positive cancer stem cells (CSCs) led to an uneven distribution of glycolytic capacity, which is crucial for understanding metabolic heterogeneity within a tumor. The rate-limiting enzyme PFKP and the metabolic probe CDG in glycolysis codistributed with the ALDH1A3 protein during the post-cell division phase, highlighting a mechanism for acquiring metabolic diversity. PKCλ deficiency reduced the asymmetric distribution of these proteins in ALDH1high cells with high ALDH1 activity, suggesting a fundamental role for PKCλ in metabolic heterogeneity. We identified 28 distinct distribution patterns combining PFKP and CDG distributions, demonstrating the complexity of glycolytic heterogeneity. Furthermore, validation and prediction of cell distribution patterns via a probabilistic model confirmed that PKCλ deficiency diminished glycolytic diversity in individual cells within a cancer cell colony generated from an ALDH1-positive CSC. These findings suggest that PKCλ-dependent asymmetric cell division of ALDH1-positive CSCs is crucial for glycolytic heterogeneity in cancer cells within a tumor, potentially offering new therapeutic targets against tumor resistance and metastasis.

DOI: https://doi.org/10.1038/s41598-025-97985-2
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr 23.

Stachydrine hydrochloride induces cell senescence and ferroptosis of castration-resistant prostate cancer.

Siyu Li, Hongwen Cao, Peng Sun, Yigeng Feng, Lei Chen, Dan Wang.

  Paclitaxel resistance of castration-resistant prostate cancer (CRPC) remains a substantial challenge in clinical oncology. Our investigation aimed to explore the potential of stachydrine hydrochloride in addressing paclitaxel resistance within CRPC. Parental prostate cancer cells, PC3 and DU145, and the corresponding paclitaxel-resistant counterparts, PC3-TxR and DU145-TxR, were subjected to indicated concentrations to determine the IC50 of paclitaxel and stachydrine hydrochloride. Cell viability and proliferation were evaluated by MTT and colony formation assays. Stachydrine hydrochloride-mediated apoptosis, senescence, and ferroptosis were detected using Western blot, SA-β-gal staining, and QuantiChrom iron assay. We found a pronounced reduction in paclitaxel resistance in both PC3-TxR and DU145-TxR cells following exposure to stachydrine hydrochloride. The considerable decrease in paclitaxel's IC50 values in these cells highlights the potential of stachydrine hydrochloride in sensitizing CRPC cells to paclitaxel-based therapies. Mechanistically, stachydrine hydrochloride treatment significantly upregulated the expression of estrogen receptor beta (ERβ) and promoted cell apoptosis, senescence, and ferroptosis pathways in CRPC. Our study provides promising insights into the potential of stachydrine hydrochloride as a novel therapeutic adjunct in overcoming paclitaxel resistance in CRPC.

Keywords:  Apoptosis; Castration-resistant prostate cancer; Ferroptosis; Senescence; Stachydrine hydrochloride

DOI:  https://doi.org/10.1007/s00210-025-04182-z
Actas Urol Esp (Engl Ed). 2025 Apr 19. pii: S2173-5786(25)00088-5. [Epub ahead of print] 501748

Gut microbiota and prostate cancer: an analysis of bacterial communities across various clinical scenarios.

M Carballo Quintá, S Perez Castro, A Freire Rodriguez, C Daviña Nuñez, A Bellas Pereira, J J Cabrera Alvargonzalez, M Perez Schoch, C A Muller Arteaga, J F Sanchez Garcia, E Cespón Outeda, E Lopez Diez.

   INTRODUCTION AND OBJECTIVES: Gut microbiota (GM) comprises a diverse community of bacteria associated with a wide range of diseases. Emerging research indicates that GM dysbiosis may affect the progression of prostate cancer (PC) and its response to treatment. This study aimed to describe GM in patients with PC at various disease stages.
MATERIALS AND METHODS: A cross-sectional study was conducted at Complejo Hospitalario Universitario de Vigo between 2023 and 2024. 49 patientes were classified into three groups: active surveillance (AS), disease-free post-treatment (DF) and advanced disease (AD). Faecal samples were obtained for GM analysis and DNA was used for 16S rRNA sequencing. The structure of the microbial community was examined via alpha and beta diversity analysis, and differential abundance was measured using the LinDA model.
RESULTS: Alpha diversity analysis revealed diminished taxon richness in patients under AS and in those treated with androgen receptor pathway in hibitors (ARPI). Beta diversity analysis indicated substantial changes attributable to the treatment group, radiation, hormone therapy, and ARPI. The AD group had a diminished number of potentially advantageous bacteria (Methanobrevibacter, Paraprevotella, Colidextribacter) and an elevated abundance of Terrisporobacter and Streptococcus compared to the DF group. The AS group showed reduction in Intestinibacter, Adlercreutzia, Subdoligranulum, and Methanobrevibacter, along with an increase in Fusicatenibacter, Lachnospiraceae, and Lachnoclostridium.
CONCLUSIONS: Patients who remain disease-free after therapy have restored microbiota abundant in potential beneficial bacteria, in contrast to individuals with severe disease or those under active monitoring. This study indicates that gut microbiome characteristics could assist in risk assessment and act as possible treatment targets for prostate cancer.

Keywords:  16S Rrna gene sequencing; Active surveillance; Alfa diversity; Beta diversity; Cáncer de próstata; Diversidad alfa; Diversidad beta; Gut microbiota; Microbiota intestinal; Prostate cancer; Secuenciación del gen 16S Rrna; Vigilancia activa

DOI:  https://doi.org/10.1016/j.acuroe.2025.501748