bims-polyam Biomed News
on Polyamines
Issue of 2022–11–20
seven papers selected by
Sebastian J. Hofer, University of Graz
  1. SnoRNP is essential for thermospermine-mediated development in Arabidopsis thaliana.
  2. Funneliformis constrictum modulates polyamine metabolism to enhance tolerance of Zea mays L. to salinity.
  3. Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function.
  4. Symmetric lipophilic polyamines exhibiting antitumor activity.
  5. A polyamine-centric, blood-based metabolite panel predictive of poor response to CAR-T cell therapy in large B cell lymphoma.
  6. Supplementation of nitric oxide and spermidine alleviates the nickel stress-induced damage to growth, chlorophyll metabolism, and photosynthesis by upregulating ascorbate-glutathione and glyoxalase cycle functioning in tomato.
  7. Spermidine rejuvenates T lymphocytes and restores anticancer immunosurveillance in aged mice.
  1. Sci China Life Sci. 2022 Nov 15.
    SnoRNP is essential for thermospermine-mediated development in Arabidopsis thaliana.
    Xilong Li, Zongyun Yan, Meiling Zhang, Jiayin Wang, Peiyong Xin, Shujing Cheng, Liquan Kou, Xiaoting Zhang, Songlin Wu, Jinfang Chu, Chengqi Yi, Keqiong Ye, Bing Wang, Jiayang Li.
      Polyamines have been discovered for hundreds of years and once considered as a class of phytohormones. Polyamines play critical roles in a range of developmental processes. However, the molecular mechanisms of polyamine signaling pathways remain poorly understood. Here, we measured the contents of main types of polyamines, and found that endogenous level of thermospermine (T-Spm) in Arabidopsis thaliana is comparable to those of classic phytohormones and is significantly lower than those of putrescine (Put), spermidine (Spd), and spermine (Spm). We further found a nodule-like structure around the junction area connecting the shoot and root of the T-Spm biosynthetic mutant acl5 and obtained more than 50 suppressors of acl5nodule structure (san) through suppressor screening. An in-depth study of two san suppressors revealed that NAP57 and NOP56, core components of box H/ACA and C/D snoRNPs, were essential for T-Spm-mediated nodule-like structure formation and plant height. Furthermore, analyses of rRNA modifications showed that the overall levels of pseudouridylation and 2'-O-methylation were compromised in san1 and san2 respectively. Taken together, these results establish a strong genetic relationship between rRNA modification and T-Spm-mediated growth and development, which was previously undiscovered in all organisms.
    Keywords:  2′-O-methylation; Arabidopsis thaliana; polyamines; pseudouridylation; snoRNP; thermospermine
    DOI:  https://doi.org/10.1007/s11427-022-2235-4
  2. Microbiol Res. 2022 Nov 04. pii: S0944-5013(22)00294-4. [Epub ahead of print]266 127254
    Funneliformis constrictum modulates polyamine metabolism to enhance tolerance of Zea mays L. to salinity.
    Ahmed M El-Sawah, Ghada G Abdel-Fattah, Paul Holford, Shereen Magdy Korany, Emad A Alsherif, Hamada AbdElgawad, Zaid Ulhassan, Izabela Jośko, Basharat Ali, Mohamed S Sheteiwy.
      The mechanisms underlie increased stress tolerance in plants of salinity stress in plants by arbuscular mycorrhizal fungi (AMF) are poorly understood, particularly the role of polyamine metabolism. The current study was conducted to investigate how inoculation with the AMF, Funneliformis constrictum, affects maize plant tolerance to salt stress. To this end, we investigated the changes in photosynthesis, redox status, primary metabolites (amino acids) and secondary metabolism (phenolic and polyamine metabolism). Control and inoculated maize plants were grown using different concentrations of diluted seawater (0%, 10%, 20% and 40%). Results revealed that treatment with 10% seawater had a beneficial effect on AMF and its host growth. However, irrigation with 20% and 40% significantly reduced plant growth and biomass. As seawater concentration increased, the plants' reliance on mycorrhizal fungi increased resulting in enhanced growth and photosynthetic pigments contents. Under higher seawater concentrations, inoculation with AMF reduced salinity induced oxidative stress and supported redox homeostasis by reducing H2O2 and MDA levels as well as increasing antioxidant-related enzymes activities (e.g., CAT, SOD, APX, GPX, POX, GR, and GSH). AMF inoculation increased amino acid contents in shoots and roots under control and stress conditions. Amino acids availability provides a route for polyamines biosynthesis, where AMF increased polyamines contents (Put, Spd, Spm, total Pas) and their metabolic enzymes associated (ADC, SAMDC, Spd synthase, and Spm synthase), particularly under 40% seawater irrigation. Consistently, the transcription of genes, involved in polyamine metabolism was also up regulated in salinity-stressed plants. AMF further increased the expression in genes involved in polyamine biosynthesis (ODC, SAMDC, SPDS2 and decreased expression of those in catabolic biosynthesis (ADC and PAO). Overall, inoculation with Funneliformis constrictum could be adopted as a practical strategy to alleviate salinity stress.
    Keywords:  Arbuscular mycorrhizal fungi; Colonization; Maize; Polyamines; Seawater
    DOI:  https://doi.org/10.1016/j.micres.2022.127254
  3. J Med Chem. 2022 Nov 16.
    Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function.
    Aiste Dobrovolskaite, Holly Moots, Mukund P Tantak, Kunal Shah, Jenna Thomas, Sharifa Dinara, Chelsea Massaro, Paul M Hershberger, Patrick R Maloney, Satyamaheshwar Peddibhotla, Eliot Sugarman, Sally Litherland, Juan Pablo Arnoletti, Rajiv Kumar Jha, David Levens, Otto Phanstiel.
      Polyamine biosynthesis is regulated by ornithine decarboxylase (ODC), which is transcriptionally activated by c-Myc. A large library was screened to find molecules that potentiate the ODC inhibitor, difluoromethylornithine (DFMO). Anthranilic acid derivatives were identified as DFMO adjunct agents. Further studies identified the far upstream binding protein 1 (FUBP1) as the target of lead compound 9. FUBP1 is a single-stranded DNA/RNA binding protein and a master controller of specific genes including c-Myc and p21. We showed that 9 does not inhibit 3H-spermidine uptake yet works synergistically with DFMO to limit cell growth in the presence of exogenous spermidine. Compound 9 was also shown to inhibit the KH4 FUBP1-FUSE interaction in a gel shift assay, bind to FUBP1 in a ChIP assay, reduce both c-Myc mRNA and protein expression, increase p21 mRNA and protein expression, and deplete intracellular polyamines. This promising hit opens the door to new FUBP1 inhibitors with increased potency.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c01350
  4. Bioorg Med Chem. 2022 Nov 05. pii: S0968-0896(22)00482-5. [Epub ahead of print]76 117089
    Symmetric lipophilic polyamines exhibiting antitumor activity.
    Ksenia A Perevoshchikova, Elizaveta A Eshtukova-Shcheglova, Oleg V Markov, Andrey V Markov, Ivan V Chernikov, Mikhail A Maslov, Marina A Zenkova.
      Unsymmetric lipophilic polyamine derivatives are considered as potential antitumor agents. Here, a series of novel symmetric lipophilic polyamines (LPAs) based on norspermine and triethylenetetramine (TETA) backbones bearing alkyl substituents with different lengths (from decyl to octadecyl) at C(1) atom of glycerol were synthesized. Performed screening of the cytotoxicity of novel compounds on the panel of tumor cell lines (MCF-7, KB-3-1, B16) and non-malignant fibroblasts hFF3 in vitro revealed a correlation between the length of the aliphatic moieties in LPAs and their toxic effects - LPAs with the shortest decyl substituent were found to exhibit the highest cytotoxicity. Furthermore, norspermine-based LPAs displayed somewhat more pronounced cytotoxicity compared with their TETA-based counterparts. Further mechanistic studies demonstrated that hit LPAs containing the norspermine backbone and tetradecyl or decyl substituents efficiently induced apoptosis in KB-3-1 cells. Moreover, decyl-bearing LPA inhibited motility and enhanced adhesiveness of murine B16 melanoma cells in vitro, showing promising antimetastatic potential. Thus, developed novel symmetric norspermine-based LPAs can be considered as promising anticancer chemotherapeutic candidates.
    Keywords:  Alkyl cationic glycerolipids; Cancer; Lipids; Lipopolyamine; Polyamine metabolism
    DOI:  https://doi.org/10.1016/j.bmc.2022.117089
  5. Cell Rep Med. 2022 Nov 15. pii: S2666-3791(22)00263-4. [Epub ahead of print]3(11): 100720
    A polyamine-centric, blood-based metabolite panel predictive of poor response to CAR-T cell therapy in large B cell lymphoma.
    Johannes F Fahrmann, Neeraj Y Saini, Chang Chia-Chi, Ehsan Irajizad, Paolo Strati, Ranjit Nair, Luis E Fayad, Sairah Ahmed, Hun Ju Lee, Swaminathan Iyer, Raphael Steiner, Jody Vykoukal, Ranran Wu, Jennifer B Dennison, Loretta Nastoupil, Preetesh Jain, Michael Wang, Michael Green, Jason Westin, Viktoria Blumenberg, Marco Davila, Richard Champlin, Elizabeth J Shpall, Partow Kebriaei, Christopher R Flowers, Michael Jain, Robert Jenq, Christoph K Stein-Thoeringer, Marion Subklewe, Sattva S Neelapu, Sam Hanash.
      Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers that resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine, and lysophospholipids, which was validated in an independent set from another institution as predictive of non-durable response to CAR-T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL.
    Keywords:  CAR-T cell therapy; biomarker; large B cell lymphoma; liquid biopsy; metabolites; prognostic
    DOI:  https://doi.org/10.1016/j.xcrm.2022.100720
  6. Front Plant Sci. 2022 ;13 1039480
    Supplementation of nitric oxide and spermidine alleviates the nickel stress-induced damage to growth, chlorophyll metabolism, and photosynthesis by upregulating ascorbate-glutathione and glyoxalase cycle functioning in tomato.
    Cheng Qin, Jie Shen, Mohammad Abass Ahanger.
      Experiments were conducted to evaluate the role of exogenously applied nitric oxide (NO; 50 µM) and spermidine (Spd; 100 µM) in alleviating the damaging effects of Ni (1 mM NiSO46H2O) toxicity on the growth, chlorophyll metabolism, photosynthesis, and mineral content in tomato. Ni treatment significantly reduced the plant height, dry mass, and the contents of glutamate 1-semialdehyde, δ-amino levulinic acid, prototoporphyrin IX, Mg-prototoporphyrin IX, total chlorophyll, and carotenoids; however, the application of NO and Spd alleviated the decline considerably. Supplementation of NO and Spd mitigated the Ni-induced decline in photosynthesis, gas exchange, and chlorophyll fluorescence parameters. Ni caused oxidative damage, while the application of NO, Spd, and NO+Spd significantly reduced the oxidative stress parameters under normal and Ni toxicity. The application of NO and Spd enhanced the function of the antioxidant system and upregulated the activity of glyoxalase enzymes, reflecting significant reduction of the oxidative effects and methylglyoxal accumulation. Tolerance against Ni was further strengthened by the accumulation of proline and glycine betaine due to NO and Spd application. The decrease in the uptake of essential mineral elements such as N, P, K, and Mg was alleviated by NO and Spd. Hence, individual and combined supplementation of NO and Spd effectively alleviates the damaging effects of Ni on tomato.
    Keywords:  antioxidants; glyoxalase; nickel; nitric oxide; oxidative stress; spermidine
    DOI:  https://doi.org/10.3389/fpls.2022.1039480
  7. Oncoimmunology. 2022 ;11(1): 2146855
    Spermidine rejuvenates T lymphocytes and restores anticancer immunosurveillance in aged mice.
    Francesca Castoldi, Guido Kroemer, Federico Pietrocola.
      Writing in Science, Al Habsi et al. show that spermidine boosts the efficacy of monoclonal antibodies targeting PD-L1 in aged tumor-bearing mice by enhancing fatty acid oxidation in CD8 T cells. These results open new therapeutic avenues to improve the effectiveness of anticancer immunotherapies in aged patients.
    Keywords:  Aging; autophagy; immune checkpoints; mitochondria
    DOI:  https://doi.org/10.1080/2162402X.2022.2146855
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