bims-polyam 2025-02-23 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2025–02–23
eight papers selected by
Sebastian J. Hofer, University of Graz

Polyamine biosynthesis dysregulation in Alzheimer's disease and Down syndrome cellular models.
The polyamine transporter ATP13A3 mediates difluoromethylornithine-induced polyamine uptake in neuroblastoma.
Heterogeneity in polyamine metabolism dictates prognosis and immune checkpoint blockade response in hepatocellular carcinoma.
eIF5A downregulated by mechanical overloading delays chondrocyte senescence and osteoarthritis by regulating the CREBBP-mediated Notch pathway.
Putrescine can inhibit germinal center B cell differentiation by inducing reactive oxygen species generation.
Jiawei Danxuan Koukang and its key component Quercetin intervened in OSF carcinogenesis by inhibiting the AR/eIF5A2 signaling pathway-mediated EMT.
Polyamine Metabolism is Dysregulated in COXFA4 Related Mitochondrial Disease.
Polyamine-Depleting Hydrogen-Bond Organic Frameworks Unleash Dendritic Cell and T Cell Vigor for Targeted CRISPR/Cas-Assisted Cancer Immunotherapy.

bioRxiv. 2025 Feb 02. pii: 2025.01.31.635912. [Epub ahead of print]

Polyamine biosynthesis dysregulation in Alzheimer's disease and Down syndrome cellular models.

Andres Sola, Alex Sandberg, Caitlin Pham, Alexandra Revier, Mia Hebinck, Alexandra Penney, Pablo Caviedes, Sunil Kumar, Ann-Charlotte Granholm, Daniel A Linseman, Daniel A Paredes.

BACKGROUND: Individuals with Down Syndrome (DS) frequently develop early onset Alzheimer's disease (AD) with pathological hallmarks closely resembling AD due to several triplicated genes on chromosome 21. Polyamines are small, organic molecules that play a pivotal role for growth and differentiation, and a dysregulation of polyamine pathways is implicated in AD pathology. However, their role in DS-associated AD is unclear.
METHODS: We analyzed polyamines and their metabolite levels in mouse hippocampal cells and human DS-AD and AD hippocampal tissue and assessed the effects of the ODC inhibitor difluoromethylornithine (DFMO) on Aβ42 aggregation and protein expression in DS fibroblasts.
RESULTS: Amyloid-β42 increased polyamine levels via ornithine decarboxylase (ODC) activation in a dose-dependent manner. DFMO reduced Aβ42 aggregation, decreased amyloid precursor protein (APP) levels, and normalized proteins linked to AD pathology in DS fibroblasts. Polyamine levels were elevated in DS-AD hippocampal tissue, with colocalization of ODC and Aβ42 aggregates.
CONCLUSION: These findings suggest that polyamine biosynthesis may exacerbate Aβ42 toxicity and APP expression, contributing to AD progression in DS. The ability of DFMO to reduce Aβ42 aggregation and restore protein homeostasis presents the polyamine pathway as a therapeutic target for DS-AD management.

DOI: https://doi.org/10.1101/2025.01.31.635912
Mol Oncol. 2025 Feb 21.

The polyamine transporter ATP13A3 mediates difluoromethylornithine-induced polyamine uptake in neuroblastoma.

Mujahid Azfar, Weiman Gao, Chris Van den Haute, Lin Xiao, Mawar Karsa, Ruby Pandher, Ayu Karsa, Dayna Spurling, Emma Ronca, Angelika Bongers, Xinyi Guo, Chelsea Mayoh, Youri Fayt, Arthur Schoofs, Mark R Burns, Steven H L Verhelst, Murray D Norris, Michelle Haber, Peter Vangheluwe, Klaartje Somers.

  High-risk neuroblastomas, often associated with MYCN protooncogene amplification, are addicted to polyamines, small polycations vital for cellular functioning. We have previously shown that neuroblastoma cells increase polyamine uptake when exposed to the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), and this mechanism is thought to limit the efficacy of the drug in clinical trials. This finding resulted in the clinical development of polyamine transport inhibitors, including AMXT 1501, which is presently under clinical investigation in combination with DFMO. However, the mechanisms and transporters involved in DFMO-induced polyamine uptake are unknown. Here, we report that knockdown of ATPase 13A3 (ATP13A3), a member of the P5B-ATPase polyamine transporter family, limited basal and DFMO-induced polyamine uptake, attenuated MYCN-amplified and non-MYCN-amplified neuroblastoma cell growth, and potentiated the inhibitory effects of DFMO. Conversely, overexpression of ATP13A3 in neuroblastoma cells increased polyamine uptake, which was inhibited by AMXT 1501, highlighting ATP13A3 as a key target of the drug. An association between high ATP13A3 expression and poor survival in neuroblastoma further supports a role of this transporter in neuroblastoma progression. Thus, this study identified ATP13A3 as a critical regulator of basal and DFMO-induced polyamine uptake and a novel therapeutic target for neuroblastoma.

Keywords:  AMXT 1501; ATP13A3; DFMO; neuroblastoma; polyamine depletion; polyamine transport inhibitor

DOI:  https://doi.org/10.1002/1878-0261.13789
Front Immunol. 2025 ;16 1516332

Heterogeneity in polyamine metabolism dictates prognosis and immune checkpoint blockade response in hepatocellular carcinoma.

Jianyan Pan, Zhong Lin, Qinchun Pan, Tao Zhu.

  Immune checkpoint blockade holds promise in hepatocellular carcinoma (HCC) treatment, but its efficacy remains limited. Dysregulated polyamine metabolism and its interaction with oncogenic pathways promote tumor progression. However, the heterogeneity of polyamine metabolism and its effects on the immune microenvironment and response to immunotherapy in HCC remain unclear. Here, we aimed to investigate the prognostic and immunotherapeutic implications of polyamine metabolism in HCC. Based on polyamine-related genes, HCC patients were categorized into two clusters with distinct survival outcomes. We developed a polyamine-related signature, termed PAscore, which was found to be a strong predictor of both poor prognosis and reduced immunocyte infiltration. Notably, a high PAscore was also associated with decreased sensitivity to immunotherapy. Within the HCC microenvironment, malignant cells exhibited polyamine metabolic heterogeneity, those with high polyamine metabolic activity showed altered hallmark pathway signatures and increased communication with myeloid cells. In vitro experiments suggested that FIRRE, the gene with the greatest impact on the PAscore, significantly contributed to HCC proliferation and metastasis. This study underscores the potential of our polyamine-related signature in predicting the prognosis and immunotherapy response in HCC patients, and also reveals the polyamine metabolic heterogeneity among HCC cells that influences their crosstalk with infiltrating myeloid cells.

Keywords:  hepatocellular carcinoma; immunotherapy; metabolic heterogeneity; polyamine; prognosis

DOI:  https://doi.org/10.3389/fimmu.2025.1516332
Bone Joint Res. 2025 Feb 20. 14(2): 124-135

eIF5A downregulated by mechanical overloading delays chondrocyte senescence and osteoarthritis by regulating the CREBBP-mediated Notch pathway.

Jialuo Huang, Jianrong Zheng, Jianbin Yin, Rengui Lin, Junfeng Wu, Hao-Ran Xu, Jinjian Zhu, Haiyan Zhang, Guiqing Wang, Daozhang Cai.

Aims: To examine how eukaryotic translation initiation factor 5A (eIF5A) regulates osteoarthritis (OA) during mechanical overload and the specific mechanism.
Methods: Histological experiments used human bone samples and C57BL/6J mice knee samples. All cell experiments were performed using mice primary chondrocytes. Messenger RNA (mRNA) sequencing was performed on chondrocytes treated with 20% cyclic tensile strain for 24 hours. Western blot (WB) and quantitative polymerase chain reaction were employed to detect relevant indicators of cartilage function in chondrocytes. We created the destabilization of the medial meniscus (DMM) model and the mechanical overload-induced OA model and injected with overexpressing eIF5A adenovirus (eIF5A-ADV). Cartilage degeneration was evaluated using Safranin O/Fast Green staining. Relative protein levels were ascertained by immunohistochemistry (IHC) and immunofluorescence (IF) staining.
Results: After OA initiation, eIF5A caused an upregulation of type II collagen (COL2) and a downregulation of matrix metalloproteinase 13 (MMP13), P16, and P21, which postponed the aggravation of OA. Further sequencing and experimental findings revealed that eIF5A knockdown accelerated the progression of OA by boosting the expression of histone acetyltransferase cyclic-adenosine monophosphate response element binding protein (CREB)-binding protein (CREBBP) to mediate activation of the Notch pathway.
Conclusion: Our findings identified a crucial functional mechanism for the onset of OA, and suggest that intra-articular eIF5A injections might be a useful therapeutic strategy for OA treatment.

DOI: https://doi.org/10.1302/2046-3758.142.BJR-2024-0288.R1
Indian J Pharmacol. 2024 Nov 01. 56(6): 430-436

Putrescine can inhibit germinal center B cell differentiation by inducing reactive oxygen species generation.

Yuqiang Zhang, Peijia Cong, Bin Wang, Haifeng Lian, Yuming Zhou.

ABSTRACT: Polyamine synthesis and abnormal regulation of B cell differentiation occur concurrently in various diseases. We investigated whether putrescine could suppress germinal center B cell (GCB) differentiation by inducing reactive oxygen species (ROS) generation. The results of flow cytometry analysis revealed that putrescine did not affect B cell apoptosis and cell cycle. The results of RT-qPCR and western blotting revealed that putrescine could inhibit CD79a phosphorylation rather than total expression. Using an O2K high-resolution respirometer, we illustrated that putrescine increased the oxygen consumption rate in the basal mitochondrial respiration stage, ATP-coupled respiration stage, and maximum respiration stage. Similarly, it also elevated ROS generation across stages in B cells and reduced the proportion of GCB cells. Meanwhile, ROS scavenging by SOD could reverse such inhibitory effects on GCB cells. We concluded that putrescine could inhibit the differentiation of GCB cells by reducing CD79a phosphorylation and increasing ROS levels in GCB cells.

DOI: https://doi.org/10.4103/ijp.ijp_531_24
Arch Oral Biol. 2025 Feb 12. pii: S0003-9969(25)00022-6. [Epub ahead of print]173 106194

Jiawei Danxuan Koukang and its key component Quercetin intervened in OSF carcinogenesis by inhibiting the AR/eIF5A2 signaling pathway-mediated EMT.

Yuzhe Dai, Chenwei Wang, Yanbo Xiao, Yisi Tan, Yao Ye, Yue Liu, Qianqi Zeng, Jin Tan.

   OBJECTIVE: This work aims to investigate the mechanism of Jiawei Danxuan Koukang (JDK) and Quercetin in oral submucous fibrosis (OSF) carcinogenesis.
DESIGN: We established an OSF model for rats by injecting Arecoline into the oral mucosa of rats to study the impact of JDK and Quercetin on the progression of OSF and OSCC. Then, the viability, proliferation, and migration ability of Arecoline-induced hOMF, CAL27 and SCC-25 cells in JDK and quercetin intervention were detected.
RESULTS: The oral mucosal epithelial cells of OSF model and OSF rats were atrophy and thinning, α-SMA, CollageI, Vimentin, Snail, AR and eukaryotic translation initiation factor 5A2 (eIF5A2) expression increased apparently, and E-cadherin expression decreased. The intervention of JDK and Quercetin reversed the changes in oral mucosal epithelial cells and OSF rats. The levels of AR in CAL27 and SCC-25 cells were higher than those in hOMF cells, and Arecoline intervention increased the levels of AR in hOMF, CAL27 and SCC-25 cells. Overexpression of AR up-regulated eIF5A2 to enhance the viability, proliferation and migration of hOMF, CAL27 and SCC-25 cells, and promoted EMT. Quercetin reversed changes in cell feature, and EMT levels in oe-AR intervention.
CONCLUSIONS: JDK and Quercetin inhibited OSF carcinogenesis by inhibiting the AR/eIF5A2 signal-mediated EMT.

Keywords:  AR/eIF5A2 signaling pathway; Jiawei Danxuan Koukang; Oral submucous fibrosis; Quercetin

DOI:  https://doi.org/10.1016/j.archoralbio.2025.106194
HGG Adv. 2025 Feb 17. pii: S2666-2477(25)00021-1. [Epub ahead of print] 100418

Polyamine Metabolism is Dysregulated in COXFA4 Related Mitochondrial Disease.

Jonathan Marquez, Stephen Viviano, Erika Beckman, Jenny Thies, Joshua Friedland-Little, Christina T Lam, Engin Deniz, Emily Shelkowitz.

Most of the chemical energy that organisms rely on to support cellular function is generated through oxidative phosphorylation, a metabolic pathway in which electron donors, NADH and FADH, are oxidized through a series of successive steps to generate adenosine triphosphate. These redox reactions are orchestrated by a series of five protein complexes that sit within the mitochondrial membrane. Deficiency of cytochrome c oxidase, the fourth of these complexes, is a recognized cause of mitochondrial disease. COXFA4, encodes one of the protein subunits of cytochrome c oxidase and variants in COXFA4 have recently been reported in individuals with a range of symptoms. These can include feeding difficulties, poor growth, cardiomyopathy, Leigh or Leigh-like disease, and neurodevelopmental delay. Though these symptoms vary widely between individuals. Yet, a mechanistic understanding of the connection between COXFA4 loss and these varied disease manifestations is lacking. Using animal modeling in Xenopus, we explored the ramifications of coxfa4 loss of function on the early developing heart. We then conducted a hypothesis naive analysis of cellular gene expression in the context of COXFA4 deletion and discovered a downstream deficiency in the ornithine decarboxylase pathway. Small molecule-based modulation of the ornithine decarboxylase pathway in our model modified the extent of disease including improvement of cardiac function. Our findings point to a mechanism by which COXFA4 dysfunction leads to tissue specific disease.

DOI: https://doi.org/10.1016/j.xhgg.2025.100418
Adv Mater. 2025 Feb 19. e2411886

Polyamine-Depleting Hydrogen-Bond Organic Frameworks Unleash Dendritic Cell and T Cell Vigor for Targeted CRISPR/Cas-Assisted Cancer Immunotherapy.

Yongchun Pan, Fei Zeng, Xiaowei Luan, Guanzhong He, Shurong Qin, Qianglan Lu, Bangshun He, Xin Han, Yujun Song.

  Polyamines have tantalized cancer researchers as a potential means to rein in the rampant growth of cancer cells. However, clinical trials in recent decades have disappointed in delivering notable progress. Herein, a microfluidic-assisted synthetic hydrogen-bond organic framework (HOF) as a polyamine-depleting nanoplatforms designed to unleash the vigor of both dendritic cells (DCs) and T cells for precision cancer immunotherapy is reported. Upon internalization by tumor cells, the loaded plasma amine oxidase (PAO) in HOF efficiently depletes polyamines, remolding the tumor microenvironment and alleviating T-cell immunosuppression. This process also generates acrolein and H2O2, triggering CRISPR-assisted neoantigen generation. Specifically, Acrolein induces carbonyl stress, increasing mutational burdens. Simultaneously, HOF leverages the energy from the bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO)-H2O2 reaction for CRET-triggered singlet oxygen production, leading to thioether bond cleavage and release CRISPR-Cas9. Once released, CRISPR-Cas9 knocks out the DNA mismatch repair (MMR)-related MLH1 gene, further elevating mutational burdens and generating neoantigens, ideal targets for DCs. This dual-action strategy not only corrects T-cell immunosuppression but also enhances DC efficacy, presenting a powerful approach for tumor immunotherapy.

Keywords:  CRISPR/Cas9; hydrogen‐bond organic framework; microfluidic; neoantigen; polyamine depletion

DOI:  https://doi.org/10.1002/adma.202411886