bims-polyam 2020-05-10 papers

on Polyamines

Issue of 2020–05–10
seven papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Difluoromethylornithine, a Decarboxylase 1 Inhibitor, Suppresses Hepatitis B Virus Replication by Reducing HBc Protein Levels.
Chemical activation of SAT1 corrects diet-induced metabolic syndrome.
Polyamines regulate gene expression by stimulating translation of histone acetyltransferase mRNAs.
Accumulation of Agmatine, Spermidine, and Spermine in Sprouts and Microgreens of Alfalfa, Fenugreek, Lentil, and Daikon Radish.
The alleviating effect of exogenous polyamines on heat stress susceptibility of different heat resistant wheat (Triticum aestivum L.) varieties.
Antisense-mediated S-adenosyl-L-methionine decarboxylase silencing affects heat stress responses of tobacco plants.
Targeting the polyamine pathway-"a means" to overcome chemoresistance in triple-negative breast cancer.

Front Cell Infect Microbiol. 2020 ;10 158

Difluoromethylornithine, a Decarboxylase 1 Inhibitor, Suppresses Hepatitis B Virus Replication by Reducing HBc Protein Levels.

Binli Mao, Zhuo Wang, Sidie Pi, Quanxin Long, Ke Chen, Jing Cui, Ailong Huang, Yuan Hu.

  Current treatments of hepatitis B virus (HBV) are limited to Interferon-alpha or the nucleos(t)ide analogs antiviral therapies, and it is crucial to develop and define new antiviral drugs to cure HBV. In this study, we explored the anti-HBV effect of difluoromethylornithine (DFMO), an irreversibly inhibitor of decarboxylase 1(ODC1) on HBV replication. Firstly, we found that polyamines contributed to HBV DNA replication via increasing levels of the HBV core protein (HBc) and capsids. In contrast, depletion of polyamines either by silencing the expression of ODC1 or DFMO treatment, resulted in decreasing viral DNA replication and levels of HBc protein and capsids. Furthermore, we found that DFMO decreased the stability of the HBc protein without affecting mRNA transcription and protein translation. Taken together, our findings demonstrate that DFMO inhibits HBV replication by reducing HBc stability and this may provide a new approach for HBV therapeutics.

Keywords:  DFMO; HBc; ODC1; hepatitis B virus; polyamines

DOI:  https://doi.org/10.3389/fcimb.2020.00158
Cell Death Differ. 2020 May 06.

Chemical activation of SAT1 corrects diet-induced metabolic syndrome.

Francesca Castoldi, Mervi T Hyvönen, Sylvère Durand, Fanny Aprahamian, Allan Sauvat, Shoaib A Malik, Elisa Elena Baracco, Erika Vacchelli, Paule Opolon, Nicolas Signolle, Déborah Lefevre, Noelie Bossut, Tobias Eisenberg, Christopher Dammbrueck, Tobias Pendl, Margerie Kremer, Sylvie Lachkar, Claudia Einer, Bernhard Michalke, Hans Zischka, Frank Madeo, Tuomo A Keinänen, Maria Chiara Maiuri, Federico Pietrocola, Guido Kroemer.

The pharmacological targeting of polyamine metabolism is currently under the spotlight for its potential in the prevention and treatment of several age-associated disorders. Here, we report the finding that triethylenetetramine dihydrochloride (TETA), a copper-chelator agent that can be safely administered to patients for the long-term treatment of Wilson disease, exerts therapeutic benefits in animals challenged with hypercaloric dietary regimens. TETA reduced obesity induced by high-fat diet, excessive sucrose intake, or leptin deficiency, as it reduced glucose intolerance and hepatosteatosis, but induced autophagy. Mechanistically, these effects did not involve the depletion of copper from plasma or internal organs. Rather, the TETA effects relied on the activation of an energy-consuming polyamine catabolism, secondary to the stabilization of spermidine/spermine N1-acetyltransferase-1 (SAT1) by TETA, resulting in enhanced enzymatic activity of SAT. All the positive effects of TETA on high-fat diet-induced metabolic syndrome were lost in SAT1-deficient mice. Altogether, these results suggest novel health-promoting effects of TETA that might be taken advantage of for the prevention or treatment of obesity.

DOI: https://doi.org/10.1038/s41418-020-0550-z
J Biol Chem. 2020 May 06. pii: jbc.RA120.013833. [Epub ahead of print]

Polyamines regulate gene expression by stimulating translation of histone acetyltransferase mRNAs.

Akihiko Sakamoto, Yusuke Terui, Takeshi Uemura, Kazuei Igarashi, Keiko Kashiwagi.

  Polyamines regulate gene expression in Escherichia coli by translationally stimulating mRNAs encoding global transcription factors. In this study, we focused on histone acetylation, one of the mechanisms of epigenetic regulation of gene expression, to attempt to clarify the role of polyamines in the regulation of gene expression in eukaryotes. We found that activities of histone acetyltransferases in both the nucleus and cytoplasm decreased significantly in polyamine-reduced mouse mammary carcinoma FM3A cells. Although protein levels of histones H3 and H4 did not change in control and polyamine-reduced cells, acetylation of histones H3 and H4 was greatly decreased in the polyamine-reduced cells. Next, we used control and polyamine-reduced cells to identify histone acetyltransferases whose synthesis is stimulated by polyamines. We found that polyamines stimulate the translation of histone acetyltransferases GCN5 and HAT1. Accordingly, GCN5- and HAT1-catalyzed acetylation of specific lysine residues on histones H3 and H4 was stimulated by polyamines. Consistent with these findings, transcription of genes required for cell proliferation was enhanced by polyamines. These results indicate that polyamines regulate gene expression by enhancing the expression of the histone acetyltransferases GCN5 and HAT1 at the level of translation. Mechanistically, polyamines enhanced the interaction of microRNA-7648-5p (miR-7648-5p) with the 5'-UTR of GCN5 mRNA, resulting in stimulation of translation due to the destabilization of the dsRNA between the 5'-UTR and the ORF of GCN5 mRNA. Because HAT1 mRNA has a short 5'-UTR, polyamines may enhance initiation complex formation directly on this mRNA.

Keywords:  gene expression; histone acetylase; histone acetyltransferase 1 (HAT1); histone acetyltransferase GCN5 (GCN5); histone modification; miR-7648-5p; polyamine; polyamine modulon; spermidine; translation regulation

DOI:  https://doi.org/10.1074/jbc.RA120.013833
Foods. 2020 May 01. pii: E547. [Epub ahead of print]9(5):

Accumulation of Agmatine, Spermidine, and Spermine in Sprouts and Microgreens of Alfalfa, Fenugreek, Lentil, and Daikon Radish.

Irena Kralj Cigić, Sašo Rupnik, Tjaša Rijavec, Nataša Poklar Ulrih, Blaž Cigić.

  Sprouts and microgreens are a rich source of various bioactive compounds. Seeds of lentil, fenugreek, alfalfa, and daikon radish seeds were germinated and the contents of the polyamines agmatine (AGM), putrescine (PUT), cadaverine (CAD), spermidine (SPD), and spermine (SPM) in ungerminated seeds, sprouts, and microgreens were determined. In general, sprouting led to the accumulation of the total polyamine content. The highest levels of AGM (5392 mg/kg) were found in alfalfa microgreens, PUT (1079 mg/kg) and CAD (3563 mg/kg) in fenugreek sprouts, SPD (579 mg/kg) in lentil microgreens, and SPM (922 mg/kg) in fenugreek microgreens. A large increase in CAD content was observed in all three legume sprouts. Conversely, the nutritionally beneficial polyamines AGM, SPD, and SPM were accumulated in microgreens, while their contents of CAD were significantly lower. In contrast, daikon radish sprouts exhibited a nutritionally better profile of polyamines than the microgreens. Freezing and thawing of legume sprouts resulted in significant degradation of CAD, PUT, and AGM by endogenous diamine oxidases. The enzymatic potential of fenugreek sprouts can be used to degrade exogenous PUT, CAD, and tyramine at pH values above 5.

Keywords:  biogenic amines; diamine oxidase; germination; lens culinaris; medicago sativa; polyamines; raphanus sativus; trigonella foenum-graecum

DOI:  https://doi.org/10.3390/foods9050547
Sci Rep. 2020 May 04. 10(1): 7467

The alleviating effect of exogenous polyamines on heat stress susceptibility of different heat resistant wheat (Triticum aestivum L.) varieties.

Jianguo Jing, Suyan Guo, Youfang Li, Weihua Li.

High temperature inhibits wheat grain filling. Polyamines (PAs) are closely associated with plant resistance caused by abiotic stress. However, little is known about the effect of PAs on the grain filling of wheat under heat stress. Two wheat varieties differing in heat resistance were used, and endogenous PAs levels were measured during grain filling under normal growth conditions outside the greenhouse (CK), artificially simulated high temperature (HT), artificially simulated high temperature plus exogenous application of spermine (HT + Spm) and artificially simulated high temperature plus spermidine (HT + Spd) treatments. Additionally, the variation of antioxidant enzymatic activities and osmotic adjustable substances content in grains was measured during grain filling. The results showed that compared with HT,HT + Spm and HT + Spd significantly increased grain weight of XC 6 (heat-resistant variety) by 19% and 5%, and XC 31 (heat-sensitive variety) by 31% and 34%, activity of superoxide dismutase (SOD), peroxidase (POD)and catalase (CAT) and content of Spm, Spd, and proline (Pro) increased significantly, while putrescine (Put), malondialdehyde (MDA) and soluble sugar (SS)contentdecreased during grain filling; The correlation analysis showed that grain weight was negatively correlated with the content of PUT, MDA, Pro and activity of SOD and CAT and positively correlated with the content of Spd and activity of POD in grains. Our results indicated that exogenous Spm and Spd could alleviate the heat injury of grain filling.

DOI: https://doi.org/10.1038/s41598-020-64468-5
Funct Plant Biol. 2020 May 07.

Antisense-mediated S-adenosyl-L-methionine decarboxylase silencing affects heat stress responses of tobacco plants.

Ifigeneia Mellidou, Katerina Karamanoli, Helen-Isis A Constantinidou, Kalliopi A Roubelakis-Angelakis.

Understanding the molecular mode(s) of plant tolerance to heat stress (HS) is crucial since HS is a potential threat to sustainable agriculture and global crop production. Polyamines (PAs) seem to exert multifaceted effects in plant growth and development and responses to abiotic and biotic stresses, presumably via their homeostasis, chemical interactions and contribution to hydrogen peroxide (H2O2) cellular 'signatures'. Downregulation of the apoplastic POLYAMINE OXIDASE (PAO) gene improved thermotolerance in tobacco (Nicotiana tabacum L.) transgenics. However, in the present work we show that transgenic tobacco plants with antisense-mediated S-ADENOSYL-L-METHIONINE DECARBOXYLASE silencing (AS-NtSAMDC) exhibited enhanced sensitivity and delayed responses to HS which was accompanied by profound injury upon HS removal (recovery), as assessed by phenological, physiological and biochemical characteristics. In particular, the AS-NtSAMDC transgenics exhibited significantly reduced rate of photosynthesis, as well as enzymatic and non-enzymatic antioxidants. These transgenics suffered irreversible damage, which significantly reduced their growth potential upon return to normal conditions. These data reinforce the contribution of increased PA homeostasis to tolerance, and can move forward our understanding on the PA-mediated mechanism(s) conferring tolerance to HS that might be targeted via traditional or biotechnological breeding for developing HS tolerant plants.

DOI: https://doi.org/10.1071/FP19350
J Biol Chem. 2020 May 08. 295(19): 6278-6279

Targeting the polyamine pathway-"a means" to overcome chemoresistance in triple-negative breast cancer.

Colleen Sweeney.

Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance.

DOI: https://doi.org/10.1074/jbc.H120.013736