bims-polyam 2022-08-28 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2022–08–28
eight papers selected by
Sebastian J. Hofer, University of Graz

Histone deacetylase 10 liberates spermidine to support polyamine homeostasis and tumor cell growth.
Polyamine-Based Nanostructures Share Polyamine Transport Mechanisms with Native Polyamines and Their Analogues: Significance for Polyamine-Targeted Therapy.
Polyamine and Ethanolamine Metabolism in Bacteria as an Important Component of Nitrogen Assimilation for Survival and Pathogenicity.
Recent Advances in Fluorescent Methods for Polyamine Detection and the Polyamine Suppressing Strategy in Tumor Treatment.
A systematic exploration reveals the potential of spermidine for hypopigmentation treatment through the stabilization of melanogenesis-associated proteins.
The role of ethylene signalling in the regulation of salt stress response in mature tomato fruits: Metabolism of antioxidants and polyamines.
Effects of Spermidine on Gut Microbiota Modulation in Experimental Abdominal Aortic Aneurysm Mice.
Genome-Wide Identification and Functional Analysis of Polyamine Oxidase Genes in Maize Reveal Essential Roles in Abiotic Stress Tolerance.

J Biol Chem. 2022 Aug 18. pii: S0021-9258(22)00850-X. [Epub ahead of print] 102407

Histone deacetylase 10 liberates spermidine to support polyamine homeostasis and tumor cell growth.

Tracy Murray Stewart, Jackson R Foley, Cassandra E Holbert, Glynis Klinke, Gernot Poschet, Raphael R Steimbach, Aubry K Miller, Robert A Casero.

  Cytosolic histone deacetylase-10 (HDAC10) specifically deacetylates the modified polyamine N8-acetylspermidine (N8-AcSpd). Although intracellular concentrations of N8-AcSpd are low, extracellular sources can be abundant, particularly in the colonic lumen. Extracellular polyamines, including those from the diet and microbiota, can support tumor growth both locally and at distant sites. However, the contribution of N8-AcSpd in this context is unknown. We hypothesized that HDAC10, by converting N8- AcSpd to spermidine, may provide a source of this growth-supporting polyamine in circumstances of reduced polyamine biosynthesis, such as in polyamine-targeting anticancer therapies. Inhibitors of polyamine biosynthesis, including α-difluoromethylornithine (DFMO), inhibit tumor growth, but compensatory uptake of extracellular polyamines has limited their clinical success. Combining DFMO with inhibitors of polyamine uptake have improved the antitumor response. However, acetylated polyamines may use different transport machinery than the parent molecules. Here, we use CRISPR/Cas9-mediated HDAC10-knockout cell lines and HDAC10-specific inhibitors to investigate the contribution of HDAC10 in maintaining tumor cell proliferation. We demonstrate inhibition of cell growth by DFMO-associated polyamine depletion is successfully rescued by exogenous N8-AcSpd (at physiological concentrations), which is converted to spermidine and spermine, only in cell lines with HDAC10 activity. Furthermore, we show loss of HDAC10 prevents both restoration of polyamine levels and growth rescue, implicating HDAC10 in supporting polyamine-associated tumor growth. These data suggest the utility of HDAC10-specific inhibitors as an antitumor strategy that may have value in improving the response to polyamine-blocking therapies. Additionally, the cell-based assay developed in this study provides an inexpensive, high-throughput method of screening potentially selective HDAC10 inhibitors.

Keywords:  N8-acetylspermidine; Polyamine; colorectal cancer; difluoromethylornithine (DFMO); histone deacetylase 10 (HDAC10); metabolism; microbiome; polyamine-blocking therapy; spermidine; tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.jbc.2022.102407
Med Sci (Basel). 2022 Aug 22. pii: 44. [Epub ahead of print]10(3):

Polyamine-Based Nanostructures Share Polyamine Transport Mechanisms with Native Polyamines and Their Analogues: Significance for Polyamine-Targeted Therapy.

Cassandra E Holbert, Jackson R Foley, Ao Yu, Tracy Murray Stewart, Otto Phanstiel, David Oupicky, Robert A Casero.

  Polyamines are small polycationic alkylamines involved in many fundamental cellular processes, including cell proliferation, survival, and protection from oxidative stress. Polyamine homeostasis is tightly regulated through coordinated biosynthesis, catabolism, and transport. Due to their continual proliferation, cancer cells maintain elevated intracellular polyamine pools. Both polyamine metabolism and transport are commonly dysregulated in cancer, and as such, polyamine analogues are a promising strategy for exploiting the increased polyamine requirement of cancer cells. One potential polyamine analogue resistance mechanism is the downregulation of the poorly defined polyamine transport system. Recent advances in nanomedicine have produced nanostructures with polyamine analogue-based backbones (nanopolyamines). Similar nanostructures with non-polyamine backbones have been shown to be transported by endocytosis. As these polyamine-based nanoparticles could be a method for polyamine analogue delivery that bypasses polyamine transport, we designed the current studies to determine the efficacy of polyamine-based nanoparticles in cells lacking intact polyamine transport. Utilizing polyamine transport-deficient derivatives of lung adenocarcinoma lines, we demonstrated that cells unable to transport natural polyamines were also resistant to nanopolyamine-induced cytotoxicity. This resistance was a result of transport-deficient cells being incapable of importing and accumulating nanopolyamines. Pharmacological modulation of polyamine transport confirmed these results in polyamine transport competent cells. These studies provide additional insight into the polyamine transport pathway and suggest that receptor-mediated endocytosis is a likely mechanism of transport for higher-order polyamines, polyamine analogues and the nanopolyamines.

Keywords:  cancer therapy; drug delivery system; drug transport; nanoparticle; nanopolyamine; polyamine; polyamine analogue; polyamine transport

DOI:  https://doi.org/10.3390/medsci10030044
Med Sci (Basel). 2022 Jul 29. pii: 40. [Epub ahead of print]10(3):

Polyamine and Ethanolamine Metabolism in Bacteria as an Important Component of Nitrogen Assimilation for Survival and Pathogenicity.

Sergii Krysenko, Wolfgang Wohlleben.

  Nitrogen is an essential element required for bacterial growth. It serves as a building block for the biosynthesis of macromolecules and provides precursors for secondary metabolites. Bacteria have developed the ability to use various nitrogen sources and possess two enzyme systems for nitrogen assimilation involving glutamine synthetase/glutamate synthase and glutamate dehydrogenase. Microorganisms living in habitats with changeable availability of nutrients have developed strategies to survive under nitrogen limitation. One adaptation is the ability to acquire nitrogen from alternative sources including the polyamines putrescine, cadaverine, spermidine and spermine, as well as the monoamine ethanolamine. Bacterial polyamine and monoamine metabolism is not only important under low nitrogen availability, but it is also required to survive under high concentrations of these compounds. Such conditions can occur in diverse habitats such as soil, plant tissues and human cells. Strategies of pathogenic and non-pathogenic bacteria to survive in the presence of poly- and monoamines offer the possibility to combat pathogens by using their capability to metabolize polyamines as an antibiotic drug target. This work aims to summarize the knowledge on poly- and monoamine metabolism in bacteria and its role in nitrogen metabolism.

Keywords:  bacteria; drug discovery; ethanolamine metabolism; nitrogen assimilation; polyamine metabolism

DOI:  https://doi.org/10.3390/medsci10030040
Biosensors (Basel). 2022 Aug 12. pii: 633. [Epub ahead of print]12(8):

Recent Advances in Fluorescent Methods for Polyamine Detection and the Polyamine Suppressing Strategy in Tumor Treatment.

Bingli Lu, Lingyun Wang, Xueguang Ran, Hao Tang, Derong Cao.

  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.

Keywords:  detection; polyamines; suppressor strategies; tumor

DOI:  https://doi.org/10.3390/bios12080633
Sci Rep. 2022 Aug 25. 12(1): 14478

A systematic exploration reveals the potential of spermidine for hypopigmentation treatment through the stabilization of melanogenesis-associated proteins.

Sofia Brito, Hyojin Heo, Byungsun Cha, Su-Hyun Lee, Sehyun Chae, Mi-Gi Lee, Byeong-Mun Kwak, Bum-Ho Bin.

Spermidine (SPD), a polyamine naturally present in living organisms, is known to prolong the lifespan of animals. In this study, the role of SPD in melanogenesis was investigated, showing potential as a pigmenting agent. SPD treatment increased melanin production in melanocytes in a dose dependent manner. Computational analysis with RNA-sequencing data revealed the alteration of protein degradation by SPD treatment without changes in the expressions of melanogenesis-related genes. Indeed, SPD treatment significantly increased the stabilities of tyrosinase-related protein (TRP)-1 and -2 while inhibiting ubiquitination, which was confirmed by treatment of proteasome inhibitor MG132. Inhibition of protein synthesis by cycloheximide (CHX) showed that SPD treatment increased the resistance of TRP-1 and TRP-2 to protein degradation. To identify the proteins involved in SPD transportation in melanocytes, the expression of several solute carrier (SLC) membrane transporters was assessed and, among 27 transporter genes, SLC3A2, SLC7A1, SLC18B1, and SLC22A18 were highly expressed, implying they are putative SPD transporters in melanocytes. Furthermore, SLC7A1 and SLC22A18 were downregulated by SPD treatment, indicating their active involvement in polyamine homeostasis. Finally, we applied SPD to a human skin equivalent and observed elevated melanin production. Our results identify SPD as a potential natural product to alleviate hypopigmentation.

DOI: https://doi.org/10.1038/s41598-022-18629-3
J Plant Physiol. 2022 Aug 14. pii: S0176-1617(22)00179-1. [Epub ahead of print]277 153793

The role of ethylene signalling in the regulation of salt stress response in mature tomato fruits: Metabolism of antioxidants and polyamines.

Zoltán Takács, Zalán Czékus, Irma Tari, Péter Poór.

  Salt stress-induced ethylene (ET) can influence the defence responses of plants that can be dependent on plant organs. In this work, the effects of salt stress evoked by 75 mM NaCl treatment were measured in fruits of wild-type (WT) and ET receptor-mutant Never ripe (Nr) tomato. Salt stress reduced the weight and size of fruits both in WT and Nr, which proved to be more pronounced in mutants. In addition, significantly higher H2O2 levels and lipid peroxidation were measured after the salt treatment in Nr as compared to the untreated control than in WT. ET regulated the key antioxidant enzymes, especially ascorbate peroxidase (APX), in WT but in the mutant fruits the activity of APX did not change and the superoxide dismutase and catalase activities were downregulated compared to untreated controls after salt treatment contributing to a higher degree of oxidative stress in Nr fruits. The dependency of PA metabolism on the active ET signalling was investigated for the first time in fruits of Nr mutants under salt stress. 75 mM NaCl enhanced the accumulation of spermine in WT fruits, which was not observed in Nr, but levels of putrescine and spermidine were elevated by salt stress in these tissues. Moreover, the catabolism of PAs was much stronger under high salinity in Nr fruits contributing to higher oxidative stress, which was only partially alleviated by the increased total and reduced ascorbate and glutathione pool. We can conclude that ET-mediated signalling plays a crucial role in the regulation of salt-induced oxidative stress and PA levels in tomato fruits at the mature stage.

Keywords:  Antioxidants; Ethylene; Fruit; Never ripe; Polyamines; Tomato

DOI:  https://doi.org/10.1016/j.jplph.2022.153793
Nutrients. 2022 Aug 16. pii: 3349. [Epub ahead of print]14(16):

Effects of Spermidine on Gut Microbiota Modulation in Experimental Abdominal Aortic Aneurysm Mice.

Shuai Liu, Yu Liu, Jiani Zhao, Pu Yang, Wei Wang, Mingmei Liao.

  Accumulating evidence in recent years has demonstrated the important role of gut microbiota in maintaining cardiovascular function. However, their functions in abdominal aortic aneurysm (AAA) are largely unexplored. In this study, we established a porcine pancreatic elastase-infused experimental AAA mouse model and explored gut microbiota modulation using 16S rDNA sequencing. Here, we found that a significant alteration to gut microbiota composition and function occurred in AAA. The functional change in the gut microbiome revealed dysregulated biosynthesis metabolism and transport of spermidine in AAA. Furthermore, exogenous spermidine was administrated via drinking water and attenuated the progression of experimental AAA disease, which supports our recent study that spermidine alleviates systemic inflammation and AAA. These effects were associated with remitted gut microbiota dysbiosis and metabolism in AAA progression as demonstrated by 16S rDNA gene analysis. In addition, several bacterial florae, such as Bacteroides, Parabacteroides and Prevotella, were identified to be associated with the progression of AAA. Our results uncovered altered gut microbial profiles in AAA and highlighted the potential therapeutic use of spermidine in the treatment of gut microbiota dysbiosis and AAA.

Keywords:  abdominal aortic aneurysm; aortic disease; gut microbiota; polyamines metabolism; spermidine

DOI:  https://doi.org/10.3390/nu14163349
Front Plant Sci. 2022 ;13 950064

Genome-Wide Identification and Functional Analysis of Polyamine Oxidase Genes in Maize Reveal Essential Roles in Abiotic Stress Tolerance.

Yan Xi, Wenjing Hu, Yue Zhou, Xiang Liu, Yexiong Qian.

  Polyamines (PAs) play a critical role in growth and developmental processes and stress responses in plants. Polyamine oxidase (PAO) is a flavin adenine dinucleotide (FAD)-dependent enzyme that plays a major role in PA catabolism. Here, for the first time, PAO genes in maize were screened for the whole genome-wide and nine ZmPAO genes were identified in this study, named as ZmPAO1-9. Based on structural characteristics and a comparison of phylogenetic relationships of PAO gene families from seven representative species, all nine PAO proteins in maize were categorized into three distinct subfamilies. Further, chromosome location and schematic structure revealed an unevenly distribution on chromosomes and evolutionarily conserved structure features of ZmPAO genes in maize, respectively. Furthermore, transcriptome analysis demonstrated that ZmPAO genes showed differential expression patterns at diverse developmental stages of maize, suggesting that these genes may play functional developmental roles in multiple tissues. Further, through qRT-PCR validation, these genes were confirmed to be responsive to heat, drought and salinity stress treatments in three various tissues, indicating their potential roles in abiotic stress responses. Eventually, to verify the biological function of ZmPAO genes, the transgenic Arabidopsis plants overexpressing ZmPAO6 gene were constructed as a typical representative to explore functional roles in plants. The results demonstrated that overexpression of ZmPAO6 can confer enhanced heat tolerance through mediating polyamine catabolism in transgenic Arabidopsis, which might result in reduced H2O2 and MDA accumulation and alleviated chlorophyll degradation under heat stress treatment, indicating that ZmPAO6 may play a crucial role in enhancing heat tolerance of transgenic Arabidopsis through the involvement in various physiological processes. Further, the expression analysis of related genes of antioxidant enzymes including glutathione peroxidase (GPX) and ascorbate peroxidase (APX) demonstrated that ZmPAO6 can enhance heat resistance in transgenic Arabidopsis through modulating heat-induced H2O2 accumulation in polyamine catabolism. Taken together, our results are the first to report the ZmPAO6 gene response to heat stress in plants and will serve to present an important theoretical basis for further unraveling the function and regulatory mechanism of ZmPAO genes in growth, development and adaptation to abiotic stresses in maize.

Keywords:  Zea mays L.; functional analysis; polyamine oxidases; polyamines; stress response

DOI:  https://doi.org/10.3389/fpls.2022.950064