bims-polyam Biomed News
on Polyamines
Issue of 2020‒03‒29
seven papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology

  1. Biomolecules. 2020 Mar 25. pii: E499. [Epub ahead of print]10(4):
    Corral M, Wallace HM.
      Polyamines are essential growth factors that have a positive role in cancer cell growth. Their metabolic pathway and the diverse enzymes involved have been studied in depth in multiple organisms and cells. Polyamine transport also contributes to the intracellular polyamine content but this is less well-studied in mammalian cells. As the polyamine transporters could provide a means of selective drug delivery to cancer cells, a greater understanding of polyamine transport and its regulation is needed. In this study, transport of polyamines and polyamine content was measured and the effect of modulating each was determined in human colorectal cancer cells. The results provide evidence that upregulation of polyamine transport depends on polyamine depletion and on the rate of cell growth. Polyamine transport occurred in all colorectal cancer cell lines tested but to varying extents. The cell lines with the lowest basal uptake showed the greatest increase in response to polyamine depletion. Kinetic parameters for putrescine and spermidine suggest the existence of two separate transporters. Transport was shown to be a saturable but non-polarised process that can be regulated both positively and negatively. Using the polyamine transporter to deliver anticancer drugs more selectively is now a reality, and the ability to manipulate the polyamine transport process increases the possibility of using these transporters therapeutically.
    Keywords:  DFMO; colorectal cancer; drug delivery; polyamines; putrescine; spermidine; transport; uptake
  2. PLoS One. 2020 ;15(3): e0230844
    Martín-Vicente M, González-Riaño C, Barbas C, Jiménez-Sousa MÁ, Brochado-Kith O, Resino S, Martínez I.
      Viral infections induce substantial metabolic changes in infected cells to optimize viral production while cells develop countermeasures to restrict that infection. Human respiratory syncytial virus (HRSV) is an infectious pathogen that causes severe lower respiratory tract infections (LRTI) in infants, the elderly, and immunocompromised adults for which no effective treatment or vaccine is currently available. In this study, variations in metabolite levels at different time points post-HRSV infection of epithelial cells were studied by untargeted metabolomics using liquid chromatography/mass spectrometry analysis of methanol cell extracts. Numerous metabolites were significantly upregulated after 18 hours post-infection, including nucleotides, amino acids, amino and nucleotide sugars, and metabolites of the central carbon pathway. In contrast, most lipid classes were downregulated. Additionally, increased levels of oxidized glutathione and polyamines were associated with oxidative stress in infected cells. These results show how HRSV infection influences cell metabolism to produce the energy and building blocks necessary for virus reproduction, suggesting potential therapeutic interventions against this virus.
  3. Front Pharmacol. 2020 ;11 248
    Zhang Y, Zheng Q, Zhou Y, Liu S.
      With the escalating costs in drug development, discovering new uses of approved drugs, i.e., drug repurposing, has attracted increasing interest. Spermidine and spermine are important polyamines for most cells and their biosynthesis are strictly regulated by the polyamine metabolic network. In cancerous cells and tumor environments, the concentrations of polyamines are much higher than in normal cells. During the synthesis of spermidine and spermine, an amino-propyl group is provided by decarboxylated S-adenosylmethionine, and the latter is generated from S-adenosylmethionine by AdoMetDC (AdoMet decarboxylase). Therefore, as a rate-limiting enzyme in the biosynthesis of spermidine and spermine, AdoMetDC has been an attractive drug target in cancer studies. In the last decades, many AdoMetDC inhibitors have been discovered, and several AdoMetDC inhibitors are under clinical trials, but unfortunately, none of them have been approved yet. To overcome the high costs in time and money for discovering de novo inhibitors, we set out to repurpose clinic drugs as AdoMetDC inhibitors. We used steric-clashes alleviating receptors (SCAR), a computer-aided drug discovery strategy developed by us recently for in silico screening. By combining computational screening and experimental validation, we successfully identified two approved drugs that have inhibitory potency on AdoMetDC's enzymatic activity. SCAR was previously shown to be suitable for the discovery of both covalent and non-covalent inhibitors, and this work further demonstrated the value of the SCAR strategy in drug repurposing.
    Keywords:  AdoMet decarboxylase; computer-aided drug design; drug discovery; drug repurpose; polyamines
  4. Hum Mol Genet. 2020 Mar 23. pii: ddaa047. [Epub ahead of print]
    Barca JMC, Fogazza M, Rugolo M, Chupin S, Del Dotto V, Ghelli AM, Carelli V, Simard G, Procaccio V, Bonneau D, Lenaers G, Reynier P, Zanna C.
      Interpretation of variants of uncertain significance is an actual major challenge. We addressed this question on a set of OPA1 missense variants responsible for variable severity of neurological impairments.We used targeted metabolomics to explore the different signatures of OPA1 variants expressed in Opa1 deleted mouse embryonic fibroblasts (Opa1-/- MEFs), grown under selective conditions.
    Multivariate analyses of data discriminated Opa1+/+ from Opa1-/- MEFs metabolic signatures and classified OPA1 variants according to their in-vitro severity. Indeed, the mild p.I382M hypomorphic variant was segregating close to the wild-type allele, while the most severe p.R445H variant was close to Opa1-/- MEFs, and the p.D603H and p.G439V alleles, responsible for isolated and syndromic presentations respectively, were intermediary between the p.I382M and the p.R445H variants. The most discriminant metabolic features were hydroxyproline, the spermine/spermidine ratio, amino acid pool and several phospholipids, emphasizing proteostasis, endoplasmic reticulum stress and phospholipid remodeling as the main mechanisms ranking OPA1 allele impacts on metabolism.
    These results demonstrate the high resolving power of metabolomics in hierarchizing OPA1 missense mutations by their in-vitro severity, fitting clinical expressivity. This suggests that our methodological approach can be used to discriminate the pathological significance of variants in genes responsible for other rare metabolic diseases and may be instrumental to select possible compounds eligible for supplementation treatment.
  5. Cancer Manag Res. 2020 ;12 1789-1798
    Xu F, Xu Y, Xiong JH, Zhang JH, Wu J, Luo J, Xiong JP.
      Background: AOC1 is a copper-containing amine oxidase that is responsible for catalyzing the deamination of polyamines, which produces reactive oxygen species. Previous studies have demonstrated that polyamines are involved in the regulation of proliferation, migration, and apoptosis of cells. However, very little is known about the functions and regulatory mechanisms of AOC1 in tumors.Methods: Based on GEPIA data, we found that AOC1 was significantly upregulated in human gastric cancer tissues. We knocked down AOC1 in human AGS and MKN45 cells using siRNA transfection, then utilized qRT-PCR assay and Western blot to verify the effectiveness of AOC1 knockdown in gastric cancer cells.
    Results: Function analysis demonstrated that knockdown of AOC1 inhibited the proliferation, invasion, and migration of human gastric cancer cells. Flow cytometry detection suggested that AOC1 knockdown induced apoptosis in human gastric cancer cells. Mechanism investigation suggested that AOC1 knockdown increased the ratio of Bax/Bcl2 and induced activation of the caspase cascade. Furthermore, the AKT signaling pathway was inactivated when AOC1 was silenced, including downregulated phosphorylation level of AKT and expression of downstream effectors, Cyclin D1, and p70S6K. Finally, we found that knockdown of AOC1 inhibited the epithelial-mesenchymal transition (EMT) in human gastric cancer by increasing the expression of epithelial markers E-cadherin, as well as decreasing mesenchymal marker N-cadherin, SNAIL and Slug.
    Conclusion: Our study suggests that AOC1 functions as an oncogene in human gastric cancer by activating the AKT signaling pathway and EMT process and maybe a target of 6-mercaptopurine, which provides new insight in the clinical use of AOC1 in gastric cancer therapy.
    Keywords:  AKT; AOC1; apoptosis; epithelial-mesenchymal transition; invasion and migration; proliferation
  6. PLoS One. 2020 ;15(3): e0230627
    Mastracci TL, Colvin SC, Padgett LR, Mirmira RG.
      The gene encoding eukaryotic initiation factor 5A (EIF5A) is found in diabetes-susceptibility loci in mouse and human. eIF5A is the only protein known to contain hypusine (hydroxyputrescine lysine), a polyamine-derived amino acid formed post-translationally in a reaction catalyzed by deoxyhypusine synthase (DHPS). Previous studies showed pharmacologic blockade of DHPS in type 1 diabetic NOD mice and type 2 diabetic db/db mice improved glucose tolerance and preserved beta cell mass, which suggests that hypusinated eIF5A (eIF5AHyp) may play a role in diabetes pathogenesis by direct action on the beta cells and/or altering the adaptive or innate immune responses. To translate these findings to human, we examined tissue from individuals with and without type 1 and type 2 diabetes to determine the expression of eIF5AHyp. We detected eIF5AHyp in beta cells, exocrine cells and immune cells; however, there was also unexpected enrichment of eIF5AHyp in pancreatic polypeptide-expressing PP cells. Interestingly, the presence of eIF5AHyp co-expressing PP cells was not enhanced with disease. These data identify new aspects of eIF5A biology and highlight the need to examine human tissue to understand disease.
  7. Phys Chem Chem Phys. 2020 Mar 26.
    Herrera SE, Agazzi ML, Cortez ML, Marmisollé WA, Tagliazucchi M, Azzaroni O.
      Polyamine-salt aggregates have become promising soft materials in nanotechnology due to their easy preparation process and pH-responsiveness. Here, we report the use of hexacyanoferrate(ii) and hexacyanoferrate(iii) as electroactive crosslinking agents for the formation of nanometer-sized redox-active polyamine-redox-salt aggregates (rPSA) in bulk suspension. This nanoplatform can be selectively assembled or disassembled under different stimuli such as redox environment, pH and ionic strength. By changing the charge of the building blocks, external triggers allow switching the system between two phase states: aggregate-free solution or colloidal rPSA dispersion. The stimuli-activated modulation of the assembly/disassembly processes opens a path to exploit rPSA in technologies based on smart nanomaterials.