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Biochimica Et Biophysica Acta. General... Jun 2024Polyamines not only play essential roles in cell growth and function of living organisms but are also released into the extracellular space and function as regulators of...
Polyamines not only play essential roles in cell growth and function of living organisms but are also released into the extracellular space and function as regulators of chemical transduction, although the cells from which they are released and their mode of release are not well understood. The vesicular polyamine transporter (VPAT), encoded by the SLC18B1 is responsible for the vesicular storage of spermine and spermidine, followed by their vesicular release from secretory cells. Focusing on VPAT will help identify polyamine-secreting cells and new polyamine functions. In this study, we investigated the possible involvement of VPAT in vesicular release of polyamines in MEG-01 clonal megakaryoblastic cells and platelets. RT-PCR, western blotting, and immunohistochemistry revealed VPAT expression in MEG-01 cells. MEG-01 cells secreted polyamines upon A23187 stimulation in the presence of Ca, which is temperature-dependent and sensitive to bafilomycin A. A23187-induced polyamine secretion from MEG-01 cells was reduced by treatment with reserpine, VPAT inhibitors, or VPAT RNA interference. Platelets also expressed VPAT, displaying a punctate distribution, and released spermidine upon A23187 and thrombin stimulation. These findings have demonstrated VPAT-mediated vesicular polyamine release from MEG-01 cells, suggesting the presence of similar vesicular polyamine release mechanisms in platelets.
Topics: Blood Platelets; Humans; Polyamines; Spermidine; Megakaryocytes; Megakaryocyte Progenitor Cells
PubMed: 38527572
DOI: 10.1016/j.bbagen.2024.130610 -
Biochimica Et Biophysica Acta.... Dec 2020The solute carrier 18B1 (SLC18B1) is the most recently identified gene of the vesicular amine transporter family and is conserved in the animal kingdom from insects to... (Review)
Review
The solute carrier 18B1 (SLC18B1) is the most recently identified gene of the vesicular amine transporter family and is conserved in the animal kingdom from insects to humans. Proteoliposomes containing the purified human SLC18B1 protein transport not only monoamines, but also polyamines, such as spermidine (Spd) and spermine (Spm), using an electrochemical gradient of H established by vacuolar H-ATPase (V-ATPase) as the driving force. SLC18B1 gene knockdown abolished the exocytosis of polyamines from mast cells, which affected the secretion of histamine. SLC18B1 gene knockout decreased polyamine levels by ~20% in the brain, and impaired short- and long-term memory. Thus, the SLC18B1 protein is responsible for the vesicular storage and release of polyamines, and functions as a vesicular polyamine transporter (VPAT). VPAT may define when, where, and how polyamine-mediated chemical transmission occurs, providing insights into the more versatile and complex features of amine-mediated chemical transmission than currently considered.
Topics: Animals; Brain; Cation Transport Proteins; Exocytosis; Humans; Neurotransmitter Agents; Phylogeny; Polyamines; Substrate Specificity; Synaptic Vesicles
PubMed: 32004521
DOI: 10.1016/j.bbamem.2020.183208 -
Medical Sciences (Basel, Switzerland) Apr 2022Parasites of the genus cause a variety of devastating and often fatal diseases in humans and domestic animals worldwide. The need for new therapeutic strategies is... (Review)
Review
Parasites of the genus cause a variety of devastating and often fatal diseases in humans and domestic animals worldwide. The need for new therapeutic strategies is urgent because no vaccine is available, and treatment options are limited due to a lack of specificity and the emergence of drug resistance. Polyamines are metabolites that play a central role in rapidly proliferating cells, and recent studies have highlighted their critical nature in . Numerous studies using a variety of inhibitors as well as gene deletion mutants have elucidated the pathway and routes of transport, revealing unique aspects of polyamine metabolism in parasites. These studies have also shed light on the significance of polyamines for parasite proliferation, infectivity, and host-parasite interactions. This comprehensive review article focuses on the main polyamine biosynthetic enzymes: ornithine decarboxylase, -adenosylmethionine decarboxylase, and spermidine synthase, and it emphasizes recent discoveries that advance these enzymes as potential therapeutic targets against parasites.
Topics: Animals; Leishmania; Ornithine Decarboxylase; Parasites; Polyamines; Spermidine Synthase
PubMed: 35645240
DOI: 10.3390/medsci10020024 -
Obesity Research & Clinical Practice 2021Spermidine is a natural polyamine existing in all living cells known to play an important role in cellular functions. Recently, several studies have reported the effect... (Review)
Review
Spermidine is a natural polyamine existing in all living cells known to play an important role in cellular functions. Recently, several studies have reported the effect of alterations in the spermidine pool on metabolic pathways. It has been shown that activation of spermidine/spermine N-1-acetyl-transferase (SSAT), the rate-limiting enzyme in polyamine catabolism, improved glucose and lipid metabolism. In addition, spermidine supplementation has been shown to protect against diet-induced obesity in animal models. However, some clinical studies demonstrated that polyamine levels are increased in childhood obesity and metabolic syndrome patients with type 2 diabetes (T2DM), while polyamine-rich food is associated with a lower incidence of cardiovascular disease (CVD). Therefore, this review aims to summarize and discuss the evidence from in vitro, in vivo and clinical studies on the possible roles of spermidine on metabolic pathways under physiological and obese conditions. All consistent and inconsistent findings are discussed and further studies aiming to fill any gaps in the knowledge are proposed.
Topics: Animals; Child; Diabetes Mellitus, Type 2; Glucose; Humans; Pediatric Obesity; Polyamines; Spermidine
PubMed: 34217652
DOI: 10.1016/j.orcp.2021.06.009 -
Biosensors Aug 2022The biogenic aliphatic polyamines (spermine, spermidine, and putrescine) are responsible for numerous cell functions, including cell proliferation, the stabilization of... (Review)
Review
The biogenic aliphatic polyamines (spermine, spermidine, and putrescine) are responsible for numerous cell functions, including cell proliferation, the stabilization of nucleic acid conformations, cell division, homeostasis, gene expression, and protein synthesis in living organisms. The change of polyamine concentrations in the urine or blood is usually related to the presence of malignant tumors and is regarded as a biomarker for the early diagnosis of cancer. Therefore, the detection of polyamine levels in physiological fluids can provide valuable information in terms of cancer diagnosis and in monitoring therapeutic effects. In this review, we summarize the recent advances in fluorescent methods for polyamine detection (supramolecular fluorescent sensing systems, fluorescent probes based on the chromophore reaction, fluorescent small molecules, and fluorescent nanoparticles). In addition, tumor polyamine-suppressing strategies (such as polyamine conjugate, polyamine analogs, combinations that target multiple components, spermine-responsive supramolecular chemotherapy, a combination of polyamine consumption and photodynamic therapy, etc.) are highlighted. We hope that this review promotes the development of more efficient polyamine detection methods and provides a comprehensive understanding of polyamine-based tumor suppressor strategies.
Topics: Humans; Neoplasms; Polyamines; Putrescine; Spermidine; Spermine
PubMed: 36005029
DOI: 10.3390/bios12080633 -
Medical Sciences (Basel, Switzerland) Sep 2022The polyamines putrescine, spermidine and spermine are nutrient-like polycationic molecules involved in metabolic processes and signaling pathways linked to cell growth...
The polyamines putrescine, spermidine and spermine are nutrient-like polycationic molecules involved in metabolic processes and signaling pathways linked to cell growth and cancer. One important pathway is the PI3K/Akt pathway where studies have shown that polyamines mediate downstream growth effects. Downstream of PI3K/Akt is the mTOR signaling pathway, a nutrient-sensing pathway that regulate translation initiation through 4EBP1 and p70S6K phosphorylation and, along with the PI3K/Akt, is frequently dysregulated in breast cancer. In this study, we investigated the effect of intracellular polyamine modulation on mTORC1 downstream protein and general translation state in two breast cancer cell lines, MCF-7 and MDA-MB-231. The effect of mTORC1 pathway inhibition on the growth and intracellular polyamines was also measured. Results showed that polyamine modulation alters 4EBP1 and p70S6K phosphorylation and translation initiation in the breast cancer cells. mTOR siRNA gene knockdown also inhibited cell growth and decreased putrescine and spermidine content. Co-treatment of inhibitors of polyamine biosynthesis and mTORC1 pathway induced greater cytotoxicity and translation inhibition in the breast cancer cells. Taken together, these data suggest that polyamines promote cell growth in part through interaction with mTOR pathway. Similarly intracellular polyamine content appears to be linked to mTOR pathway regulation. Finally, dual inhibition of polyamine and mTOR pathways may provide therapeutic benefits in some breast cancers.
Topics: Breast Neoplasms; Female; Humans; Mechanistic Target of Rapamycin Complex 1; Phosphatidylinositol 3-Kinases; Polyamines; Proto-Oncogene Proteins c-akt; Putrescine; RNA, Small Interfering; Ribosomal Protein S6 Kinases, 70-kDa; Spermidine; Spermine; TOR Serine-Threonine Kinases
PubMed: 36135836
DOI: 10.3390/medsci10030051 -
Physiology (Bethesda, Md.) Sep 2020Polyamines regulate a variety of physiological functions and are involved in pathogenesis of diverse human diseases. The epithelium of the mammalian gut mucosa is a... (Review)
Review
Polyamines regulate a variety of physiological functions and are involved in pathogenesis of diverse human diseases. The epithelium of the mammalian gut mucosa is a rapidly self-renewing tissue in the body, and its homeostasis is preserved through well-controlled mechanisms. Here, we highlight the roles of cellular polyamines in maintaining the integrity of the gut epithelium, focusing on the emerging evidence of polyamines in the regulation of gut epithelial renewal and barrier function. Gut mucosal growth depends on the available supply of polyamines to the dividing cells in the crypts, and polyamines are also essential for normal gut epithelial barrier function. Polyamines modulate expression of various genes encoding growth-associated proteins and intercellular junctions via distinct mechanisms involving RNA-binding proteins and noncoding RNAs. With the rapid advance of polyamine biology, polyamine metabolism and transport are promising therapeutic targets in our efforts to protect the gut epithelium and barrier function in patients with critical illnesses.
Topics: Animals; Cell Proliferation; Cell Self Renewal; Epithelial Cells; Humans; Intestinal Mucosa; Permeability; Polyamines; Signal Transduction
PubMed: 32783609
DOI: 10.1152/physiol.00011.2020 -
Cell Reports Jan 2024Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for...
Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.
Topics: Animals; Humans; Mice; Mice, Knockout; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neoplasms; Polyamines; STAT3 Transcription Factor; T-Lymphocytes
PubMed: 38175754
DOI: 10.1016/j.celrep.2023.113661 -
Microbial Pathogenesis Sep 2021The urease enzyme of Cryptococcus neoformans is linked to different metabolic pathways within the yeast cell, several of which are involved in polyamine metabolism....
The urease enzyme of Cryptococcus neoformans is linked to different metabolic pathways within the yeast cell, several of which are involved in polyamine metabolism. Cryptococcal biogenic amine production is, however, largely unexplored and is yet to be investigated in relation to urease. The aim of this study was therefore to explore and compare polyamine metabolism in wild-type, urease-negative and urease-reconstituted strains of C. neoformans. Mass spectrometry analysis showed that agmatine and spermidine were the major extra- and intracellular polyamines of C. neoformans and significant differences were observed between 26 and 37 °C. In addition, compared to the wild-type, the relative percentages of extracellular putrescine and spermidine were found to be lower and agmatine higher in cultures of the urease-deficient mutant. The inverse was true for intracellular spermidine and agmatine. Cyclohexylamine was a more potent polyamine inhibitor compared to DL-α-difluoromethylornithine and inhibitory effects were more pronounced at 37 °C than at 26 °C. At both temperatures, the urease-deficient mutant was less susceptible to cyclohexylamine treatment compared to the wild-type. For both inhibitors, growth inhibition was alleviated with polyamine supplementation. This study has provided novel insight into the polyamine metabolism of C. neoformans, highlighting the involvement of urease in biogenic amine production.
Topics: Cryptococcus neoformans; Polyamines; Putrescine; Spermidine; Urease
PubMed: 34216740
DOI: 10.1016/j.micpath.2021.105076 -
Scientific Reports Jul 2022Polyamines are small cationic molecules that have been linked to various cellular processes including replication, translation, stress response and recently, capsule...
Polyamines are small cationic molecules that have been linked to various cellular processes including replication, translation, stress response and recently, capsule regulation in Streptococcus pneumoniae (Spn, pneumococcus). Pneumococcal-associated diseases such as pneumonia, meningitis, and sepsis are some of the leading causes of death worldwide and capsule remains the principal virulence factor of this versatile pathogen. α-Difluoromethyl-ornithine (DFMO) is an irreversible inhibitor of the polyamine biosynthesis pathway catalyzed by ornithine decarboxylase and has a long history in modulating cell growth, polyamine levels, and disease outcomes in eukaryotic systems. Recent evidence shows that DFMO can also target arginine decarboxylation. Interestingly, DFMO-treated cells often escape polyamine depletion via increased polyamine uptake from extracellular sources. Here, we examined the potential capsule-crippling ability of DFMO and the possible synergistic effects of the polyamine transport inhibitor, AMXT 1501, on pneumococci. We characterized the changes in pneumococcal metabolites in response to DFMO and AMXT 1501, and also measured the impact of DFMO on amino acid decarboxylase activities. Our findings show that DFMO inhibited pneumococcal polyamine and capsule biosynthesis as well as decarboxylase activities, albeit, at a high concentration. AMXT 1501 at physiologically relevant concentration could inhibit both polyamine and capsule biosynthesis, however, in a serotype-dependent manner. In summary, this study demonstrates the utility of targeting polyamine biosynthesis and transport for pneumococcal capsule inhibition. Since targeting capsule biosynthesis is a promising way for the eradication of the diverse and pathogenic pneumococcal strains, future work will identify small molecules similar to DFMO/AMXT 1501, which act in a serotype-independent manner.
Topics: Antineoplastic Agents; Eflornithine; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Polyamines; Streptococcus pneumoniae
PubMed: 35821246
DOI: 10.1038/s41598-022-16007-7