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Nature Reviews. Cancer Nov 2018Advances in our understanding of the metabolism and molecular functions of polyamines and their alterations in cancer have led to resurgence in the interest of targeting... (Review)
Review
Advances in our understanding of the metabolism and molecular functions of polyamines and their alterations in cancer have led to resurgence in the interest of targeting polyamine metabolism as an anticancer strategy. Increasing knowledge of the interplay between polyamine metabolism and other cancer-driving pathways, including the PTEN-PI3K-mTOR complex 1 (mTORC1), WNT signalling and RAS pathways, suggests potential combination therapies that will have considerable clinical promise. Additionally, an expanding number of promising clinical trials with agents targeting polyamines for both therapy and prevention are ongoing. New insights into molecular mechanisms linking dysregulated polyamine catabolism and carcinogenesis suggest additional strategies that can be used for cancer prevention in at-risk individuals. In addition, polyamine blocking therapy, a strategy that combines the inhibition of polyamine biosynthesis with the simultaneous blockade of polyamine transport, can be more effective than therapies based on polyamine depletion alone and may involve an antitumour immune response. These findings open up new avenues of research into exploiting aberrant polyamine metabolism for anticancer therapy.
Topics: Biological Transport; Humans; Neoplasms; Polyamines; Signal Transduction
PubMed: 30181570
DOI: 10.1038/s41568-018-0050-3 -
Nature Reviews. Cancer Aug 2022The natural mammalian polyamines putrescine, spermidine and spermine are essential for both normal and neoplastic cell function and replication. Dysregulation of... (Review)
Review
The natural mammalian polyamines putrescine, spermidine and spermine are essential for both normal and neoplastic cell function and replication. Dysregulation of metabolism of polyamines and their requirements is common in many cancers. Both clinical and experimental depletion of polyamines have demonstrated their metabolism to be a rational target for therapy; however, the mechanisms through which polyamines can establish a tumour-permissive microenvironment are only now emerging. Recent data indicate that polyamines can play a major role in regulating the antitumour immune response, thus likely contributing to the existence of immunologically 'cold' tumours that do not respond to immune checkpoint blockade. Additionally, the interplay between the microbiota and associated tissues creates a tumour microenvironment in which polyamine metabolism, content and function can all be dramatically altered on the basis of microbiota composition, dietary polyamine availability and tissue response to its surrounding microenvironment. The goal of this Perspective is to introduce the reader to the many ways in which polyamines, polyamine metabolism, the microbiota and the diet interconnect to establish a tumour microenvironment that facilitates the initiation and progression of cancer. It also details ways in which polyamine metabolism and function can be successfully targeted for therapeutic benefit, including specifically enhancing the antitumour immune response.
Topics: Animals; Humans; Mammals; Neoplasms; Polyamines; Putrescine; Spermidine; Spermine; Tumor Microenvironment
PubMed: 35477776
DOI: 10.1038/s41568-022-00473-2 -
Cell Metabolism Nov 2023The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently...
The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently characterized signals from the microenvironment. Here, we showed that colonic macrophages were located directly adjacent to epithelial crypt cells in mice, where they metabolically supported epithelial cell proliferation in an mTORC1-dependent manner. Specifically, deletion of tuberous sclerosis complex 2 (Tsc2) in macrophages activated mTORC1 signaling that protected against colitis-induced intestinal damage and induced the synthesis of the polyamines spermidine and spermine. Epithelial cells ingested these polyamines and rewired their cellular metabolism to optimize proliferation and defense. Notably, spermine directly stimulated proliferation of colon epithelial cells and colon organoids. Genetic interference with polyamine production in macrophages altered global polyamine levels in the colon and modified epithelial cell proliferation. Our results suggest that macrophages act as "commensals" that provide metabolic support to promote efficient self-renewal of the colon epithelium.
Topics: Mice; Animals; Spermine; Polyamines; Colon; Intestinal Mucosa; Homeostasis; Macrophages; Mechanistic Target of Rapamycin Complex 1
PubMed: 37804836
DOI: 10.1016/j.cmet.2023.09.010 -
Microbiome Nov 2021Male fertility impaired by exogenous toxins is a serious worldwide issue threatening the health of the new-born and causing infertility. However, the metabolic...
BACKGROUND
Male fertility impaired by exogenous toxins is a serious worldwide issue threatening the health of the new-born and causing infertility. However, the metabolic connection between toxic exposures and testicular dysfunction remains unclear.
RESULTS
In the present study, the metabolic disorder of testicular dysfunction was investigated using triptolide-induced testicular injury in mice. We found that triptolide induced spermine deficiency resulting from disruption of polyamine biosynthesis and uptake in testis, and perturbation of the gut microbiota. Supplementation with exogenous spermine reversed triptolide-induced testicular dysfunction through increasing the expression of genes related to early and late spermatogenic events, as well as increasing the reduced number of offspring. Loss of gut microbiota by antibiotic treatment resulted in depletion of spermine levels in the intestine and potentiation of testicular injury. Testicular dysfunction in triptolide-treated mice was reversed by gut microbial transplantation from untreated mice and supplementation with polyamine-producing Parabacteroides distasonis. The protective effect of spermine during testicular injury was largely dependent on upregulation of heat shock protein 70s (HSP70s) both in vivo and in vitro.
CONCLUSIONS
The present study linked alterations in the gut microbiota to testicular dysfunction through disruption of polyamine metabolism. The diversity and dynamics of the gut microbiota may be considered as a therapeutic option to prevent male infertility. Video Abstract.
Topics: Animals; Gastrointestinal Microbiome; Male; Mice; Polyamines
PubMed: 34758869
DOI: 10.1186/s40168-021-01157-z -
Annual Review of Biochemistry Jun 2023The polyamines putrescine, spermidine, and spermine are abundant polycations of vital importance in mammalian cells. Their cellular levels are tightly regulated by... (Review)
Review
The polyamines putrescine, spermidine, and spermine are abundant polycations of vital importance in mammalian cells. Their cellular levels are tightly regulated by degradation and synthesis, as well as by uptake and export. Here, we discuss the delicate balance between the neuroprotective and neurotoxic effects of polyamines in the context of Parkinson's disease (PD). Polyamine levels decline with aging and are altered in patients with PD, whereas recent mechanistic studies on ATP13A2 (PARK9) demonstrated a driving role of a disturbed polyamine homeostasis in PD. Polyamines affect pathways in PD pathogenesis, such as α-synuclein aggregation, and influence PD-related processes like autophagy, heavy metal toxicity, oxidative stress, neuroinflammation, and lysosomal/mitochondrial dysfunction. We formulate outstanding research questions regarding the role of polyamines in PD, their potential as PD biomarkers, and possible therapeutic strategies for PD targeting polyamine homeostasis.
Topics: Animals; Humans; Parkinson Disease; Polyamines; Neuroprotection; Parkinsonian Disorders; Spermidine; Mammals
PubMed: 37018845
DOI: 10.1146/annurev-biochem-071322-021330 -
Proceedings of the National Academy of... Nov 2016Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative...
Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N-acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPR-cas9-mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.
Topics: Acetyltransferases; Animals; Apoptosis; Arachidonate 15-Lipoxygenase; CRISPR-Cas Systems; Carcinogenesis; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lipid Peroxidation; Metabolic Networks and Pathways; Mice; Neoplasm Proteins; Neoplasms; Oxidative Stress; Polyamines; Proto-Oncogene Proteins c-mdm2; Reactive Oxygen Species; Spermidine; Spermine; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays
PubMed: 27698118
DOI: 10.1073/pnas.1607152113 -
Cell Metabolism Aug 2019How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to...
How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5A) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis.
Topics: Animals; Cells, Cultured; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Peptide Initiation Factors; Polyamines; Proteomics; RNA-Binding Proteins; Eukaryotic Translation Initiation Factor 5A
PubMed: 31130465
DOI: 10.1016/j.cmet.2019.05.003 -
The Journal of Biological Chemistry Nov 2018Polyamines are polycationic organic amines that are required for all eukaryotic life, exemplified by the polyamine spermidine, which plays an essential role in... (Review)
Review
Polyamines are polycationic organic amines that are required for all eukaryotic life, exemplified by the polyamine spermidine, which plays an essential role in translation. They also play more specialized roles that differ across species, and their chemical versatility has been fully exploited during the evolution of protozoan pathogens. These eukaryotic pathogens, which cause some of the most globally widespread infectious diseases, have acquired species-specific polyamine-derived metabolites with essential cellular functions and have evolved unique mechanisms that regulate their core polyamine biosynthetic pathways. Many of these parasitic species have lost enzymes and or transporters from the polyamine metabolic pathway that are found in the human host. These pathway differences have prompted drug discovery efforts to target the parasite polyamine pathways, and indeed, the only clinically approved drug targeting the polyamine biosynthetic pathway is used to manage human African trypanosomiasis. This Minireview will primarily focus on polyamine metabolism and function in , , and species, which are the causative agents of human African trypanosomiasis (HAT) and Chagas disease, Leishmaniasis, and malaria, respectively. Aspects of polyamine metabolism across a diverse group of protozoan pathogens will also be explored.
Topics: Animals; Humans; Leishmania; Leishmaniasis; Malaria; Plasmodium; Polyamines; Trypanosoma; Trypanosomiasis, African
PubMed: 30333232
DOI: 10.1074/jbc.TM118.003342 -
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 -
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