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The Journal of Biological Chemistry Nov 2018Polyamines (PAs) are indispensable polycations ubiquitous to all living cells. Among their many critical functions, PAs contribute to the oxidative balance of the cell.... (Review)
Review
Polyamines (PAs) are indispensable polycations ubiquitous to all living cells. Among their many critical functions, PAs contribute to the oxidative balance of the cell. Beginning with studies by the Tabor laboratory in bacteria and yeast, the requirement for PAs as protectors against oxygen radical-mediated damage has been well established in many organisms, including mammals. However, PAs also serve as substrates for oxidation reactions that produce hydrogen peroxide (HO) both intra- and extracellularly. As intracellular concentrations of PAs can reach millimolar concentrations, the HO amounts produced through their catabolism, coupled with a reduction in protective PAs, are sufficient to cause the oxidative damage associated with many pathologies, including cancer. Thus, the maintenance of intracellular polyamine homeostasis may ultimately contribute to the maintenance of oxidative homeostasis. Again, pioneering studies by Tabor and colleagues led the way in first identifying spermine oxidase in They also first purified the extracellular bovine serum amine oxidase and elucidated the products of its oxidation of primary amine groups of PAs when included in culture medium. These investigations formed the foundation for many polyamine-related studies and experimental procedures still performed today. This Minireview will summarize key innovative studies regarding PAs and oxidative damage, starting with those from the Tabor laboratory and including the most recent advances, with a focus on mammalian systems.
Topics: Animals; Humans; Hydrogen Peroxide; Monoamine Oxidase; Oxidative Stress; Oxidoreductases Acting on CH-NH Group Donors; Polyamines; Polyamine Oxidase
PubMed: 30333229
DOI: 10.1074/jbc.TM118.003337 -
Nature Communications Mar 2024Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited...
Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour's metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine's conversion to polyamines, which exerts their potent ferroptosis-promoting property in an HO-dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal--iron overload--through WNT/MYC signalling, as well as the subsequent elevated polyamine synthesis, thus forming a ferroptosis-iron overload-WNT/MYC-ODC1-polyamine-HO positive feedback loop that amplifies ferroptosis. Meanwhile, we notice that ferroptotic cells release enhanced polyamine-containing extracellular vesicles into the microenvironment, thereby further sensitizing neighbouring cells to ferroptosis and accelerating the "spread" of ferroptosis in the tumour region. Besides, polyamine supplementation also sensitizes cancer cells or xenograft tumours to radiotherapy or chemotherapy through inducing ferroptosis. Considering that cancer cells are often characterized by elevated intracellular polyamine pools, our results indicate that polyamine metabolism exposes a targetable vulnerability to ferroptosis and represents an exciting opportunity for therapeutic strategies for cancer.
Topics: Humans; Polyamines; Ferroptosis; Hydrogen Peroxide; Cell Line, Tumor; Arginine; Iron Overload; Neoplasms
PubMed: 38504107
DOI: 10.1038/s41467-024-46776-w -
Oncogene Jul 2021Advancements in our understanding of polyamine molecular and cellular functions have led to increased interest in targeting polyamine metabolism for anticancer... (Review)
Review
Advancements in our understanding of polyamine molecular and cellular functions have led to increased interest in targeting polyamine metabolism for anticancer therapeutic benefits. The polyamines putrescine, spermidine, and spermine are polycationic alkylamines commonly found in all living cells and are essential for cellular growth and survival. This review summarizes the existing research on polyamine metabolism and function, specifically the role of polyamines in gastric immune cell and epithelial cell function. Polyamines have been implicated in a multitude of cancers, but in this review, we focus on the role of polyamine dysregulation in the context of Helicobacter pylori-induced gastritis and subsequent progression to gastric cancer. Due to the emerging implication of polyamines in cancer development, there is an increasing number of promising clinical trials using agents to target the polyamine metabolic pathway for potential chemoprevention and anticancer therapy.
Topics: Animals; Antineoplastic Agents; Epithelial Cells; Humans; Metabolic Networks and Pathways; Polyamines; Stomach Neoplasms
PubMed: 34108618
DOI: 10.1038/s41388-021-01862-x -
Cell Reports Jan 2022Phagocytosis of apoptotic cells, termed efferocytosis, is critical for tissue homeostasis and drives anti-inflammatory programming in engulfing macrophages. Here, we...
Phagocytosis of apoptotic cells, termed efferocytosis, is critical for tissue homeostasis and drives anti-inflammatory programming in engulfing macrophages. Here, we assess metabolites in naive and inflammatory macrophages following engulfment of multiple cellular and non-cellular targets. Efferocytosis leads to increases in the arginine-derived polyamines, spermidine and spermine, in vitro and in vivo. Surprisingly, polyamine accumulation after efferocytosis does not arise from retention of apoptotic cell metabolites or de novo synthesis but from enhanced polyamine import that is dependent on Rac1, actin, and PI3 kinase. Blocking polyamine import prevents efferocytosis from suppressing macrophage interleukin (IL)-1β or IL-6. This identifies efferocytosis as a trigger for polyamine import and accumulation, and imported polyamines as mediators of efferocytosis-induced immune reprogramming.
Topics: Animals; Apoptosis; Cytophagocytosis; Female; Healthy Volunteers; Humans; Immunomodulation; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Polyamines; Signal Transduction; Spermidine; Spermine
PubMed: 35021097
DOI: 10.1016/j.celrep.2021.110222 -
Medical Sciences (Basel, Switzerland) May 2021Polycationic polyamines are present in nearly all living organisms and are essential for mammalian cell growth and survival, and for development. These positively... (Review)
Review
Polycationic polyamines are present in nearly all living organisms and are essential for mammalian cell growth and survival, and for development. These positively charged molecules are involved in a variety of essential biological processes, yet their underlying mechanisms of action are not fully understood. Several studies have shown both beneficial and detrimental effects of polyamines on human health. In cancer, polyamine metabolism is frequently dysregulated, and elevated polyamines have been shown to promote tumor growth and progression, suggesting that targeting polyamines is an attractive strategy for therapeutic intervention. In contrast, polyamines have also been shown to play critical roles in lifespan, cardiac health and in the development and function of the brain. Accordingly, a detailed understanding of mechanisms that control polyamine homeostasis in human health and disease is needed to develop safe and effective strategies for polyamine-targeted therapy.
Topics: Cell Proliferation; Homeostasis; Humans; Neoplasms; Polyamines
PubMed: 34068137
DOI: 10.3390/medsci9020028 -
Developmental Medicine and Child... Apr 2024Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The... (Review)
Review
Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme. C-terminal truncation of ODC prevents its ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC enzyme that remains catalytically active. ODC is the first rate-limiting enzyme that converts ornithine to putrescine in the polyamine pathway. Polyamines (putrescine, spermidine, spermine) are aliphatic molecules found in all forms of life and are important during embryogenesis, organogenesis, and tumorigenesis. BABS is an ultra-rare condition with few reported cases, but it serves as a convincing example for drug repurposing therapy. α-Difluoromethylornithine (DFMO, also known as eflornithine) is an ODC inhibitor with a strong safety profile in pediatric use for neuroblastoma and other cancers as well as West African sleeping sickness (trypanosomiasis). Patients with BABS have been treated with DFMO and have shown improvement in hair growth, muscle tone, and development.
Topics: Humans; Child; Putrescine; Spermidine; Polyamines; Spermine; Eflornithine
PubMed: 37469105
DOI: 10.1111/dmcn.15687 -
The Journal of Biological Chemistry Nov 2018Polyamines are organic polycations that bind to a variety of cellular molecules, including nucleic acids. Within cells, polyamines contribute to both the efficiency and... (Review)
Review
Polyamines are organic polycations that bind to a variety of cellular molecules, including nucleic acids. Within cells, polyamines contribute to both the efficiency and fidelity of protein synthesis. In addition to directly acting on the translation apparatus to stimulate protein synthesis, the polyamine spermidine serves as a precursor for the essential post-translational modification of the eukaryotic translation factor 5A (eIF5A), which is required for synthesis of proteins containing problematic amino acid sequence motifs, including polyproline tracts, and for termination of translation. The impact of polyamines on translation is highlighted by autoregulation of the translation of mRNAs encoding key metabolic and regulatory proteins in the polyamine biosynthesis pathway, including -adenosylmethionine decarboxylase (AdoMetDC), antizyme (OAZ), and antizyme inhibitor 1 (AZIN1). Here, we highlight the roles of polyamines in general translation and also in the translational regulation of polyamine biosynthesis.
Topics: Animals; Humans; Polyamines; Protein Biosynthesis; Proteins; RNA, Messenger
PubMed: 30323064
DOI: 10.1074/jbc.TM118.003338 -
Nature Communications Feb 2021Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%....
Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduces uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO leads to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG.
Topics: Animals; Biological Transport; Brain Stem Neoplasms; Cell Death; Cell Line, Tumor; Cell Proliferation; DNA Replication; Dicarboxylic Acid Transporters; Diffuse Intrinsic Pontine Glioma; Disease Models, Animal; Eflornithine; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondrial Membrane Transport Proteins; Ornithine Decarboxylase; Polyamines
PubMed: 33579942
DOI: 10.1038/s41467-021-20896-z -
International Journal of Molecular... Sep 2019Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care... (Review)
Review
Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care patients. Mortality from acute kidney injury remains high, particularly in critically ill patients, where it can be more than 50%. The primary causes of AKI include ischemia/reperfusion (I/R), sepsis, or nephrotoxicity; however, AKI patients may present with a complicated etiology where many of the aforementioned conditions co-exist. Multiple bio-markers associated with renal damage, as well as metabolic and signal transduction pathways that are involved in the mediation of renal dysfunction have been identified as a result of the examination of models, patient samples, and clinical data of AKI of disparate etiologies. These discoveries have enhanced our ability to diagnose AKIs and to begin to elucidate the mechanisms involved in their pathogenesis. Studies in our laboratory revealed that the expression and activity of spermine/spermidine N-acetyltransferase (SAT1), the rate-limiting enzyme in polyamine back conversion, were enhanced in kidneys of rats after I/R injury. Additional studies revealed that the expression of spermine oxidase (SMOX), another critical enzyme in polyamine catabolism, is also elevated in the kidney and other organs subjected to I/R, septic, toxic, and traumatic injuries. The maladaptive role of polyamine catabolism in the mediation of AKI and other injuries has been clearly demonstrated. This review will examine the biochemical and mechanistic basis of tissue damage brought about by enhanced polyamine degradation and discuss the potential of therapeutic interventions that target polyamine catabolic enzymes or their byproducts for the treatment of AKI.
Topics: Acetyltransferases; Acute Kidney Injury; Animals; Biomarkers; Gene Expression; Gene Expression Regulation, Enzymologic; Humans; Metabolic Networks and Pathways; Oxidoreductases Acting on CH-NH Group Donors; Polyamines; Polyamine Oxidase
PubMed: 31561575
DOI: 10.3390/ijms20194790 -
Molecules (Basel, Switzerland) Nov 2023Polyamines participate in the processes of cell growth and development. The degradation branch of their metabolism involves amine oxidases. The oxidation of spermine,... (Review)
Review
Polyamines participate in the processes of cell growth and development. The degradation branch of their metabolism involves amine oxidases. The oxidation of spermine, spermidine and putrescine releases hydrogen peroxide and the corresponding aminoaldehyde. Polyamine-derived aminoaldehydes have been found to be cytotoxic, and they represent the subject of this review. 3-aminopropanal disrupts the lysosomal membrane and triggers apoptosis or necrosis in the damaged cells. It is implicated in the pathogenesis of cerebral ischemia. Furthermore, 3-aminopropanal yields acrolein through the elimination of ammonia. This reactive aldehyde is also generated by the decomposition of aminoaldehydes produced in the reaction of serum amine oxidase with spermidine or spermine. In addition, acrolein is a common environmental pollutant. It causes covalent modifications of proteins, including carbonylation, the production of Michael-type adducts and cross-linking, and it has been associated with inflammation-related diseases. APAL and acrolein are detoxified by aldehyde dehydrogenases and other mechanisms. High-performance liquid chromatography, immunochemistry and mass spectrometry have been largely used to analyze the presence of polyamine-derived aminoaldehydes and protein modifications elicited by their effect. However, the main and still open challenge is to find clues for discovering clear linkages between aldehyde-induced modifications of specific proteins and the development of various diseases.
Topics: Polyamines; Acrolein; Spermidine; Spermine; Aldehydes
PubMed: 37959847
DOI: 10.3390/molecules28217429