bims-polyam Biomed News
on Polyamines
Issue of 2021–06–13
eleven papers selected by
Sebastian J. Hofer, University of Graz



  1. Autophagy. 2021 Jun 09. 1-3
      Spermidine is a natural polyamine, central to cellular homeostasis and growth, that promotes macroautophagy/autophagy. The polyamine pathway is highly conserved from bacteria to mammals and spermidine (prominently found in some kinds of aged cheese, wheat germs, nuts, soybeans, and fermented products thereof, among others) is an intrinsic part of the human diet. Apart from nutrition, spermidine is available to mammalian organisms from intracellular biosynthesis and microbial production in the gut. Importantly, externally supplied spermidine (via drinking water or food) prolongs lifespan, activates autophagy, improves mitochondrial function, and refills polyamine pools that decline during aging in various tissues of model organisms, including mice. In two adjacent studies, we explored how dietary spermidine supplementation enhances eEF5/EIF5A hypusination, cerebral mitochondrial function and cognition in aging Drosophila melanogaster and mice.
    Keywords:  Autophagy; Drosophila; Pink1; hypusination; learning; memory; mitophagy; polyamines; spermidine
    DOI:  https://doi.org/10.1080/15548627.2021.1933299
  2. J Cell Sci. 2021 Jun 01. pii: jcs253781. [Epub ahead of print]134(11):
      In Saccharomyces cerevisiae, the selective autophagic degradation of mitochondria, termed mitophagy, is critically regulated by the adapter protein Atg32. Despite our knowledge about the molecular mechanisms by which Atg32 controls mitophagy, its physiological roles in yeast survival and fitness remains less clear. Here, we demonstrate a requirement for Atg32 in promoting spermidine production during respiratory growth and heat-induced mitochondrial stress. During respiratory growth, mitophagy-deficient yeast exhibit profound heat-stress induced defects in growth and viability due to impaired biosynthesis of spermidine and its biosynthetic precursor S-adenosyl methionine. Moreover, spermidine production is crucial for the induction of cytoprotective nitric oxide (NO) during heat stress. Hence, the re-addition of spermidine to Atg32 mutant yeast is sufficient to both enhance NO production and restore respiratory growth during heat stress. Our findings uncover a previously unrecognized physiological role for yeast mitophagy in spermidine metabolism and illuminate new interconnections between mitophagy, polyamine biosynthesis and NO signaling.
    Keywords:  ATG32; Autophagy; Mitophagy; Nitric oxide; S-adenosyl methionine; Spermidine
    DOI:  https://doi.org/10.1242/jcs.253781
  3. Cell Biosci. 2021 Jun 07. 11(1): 107
       BACKGROUND: Autophagy is required for oogenesis and plays a critical role in response to aging caused by oxidative stress. However, there have been no reports on regulation of cytoprotective autophagy in female germline stem cells (FGSCs) in response to aging caused by oxidative stress.
    RESULTS: We found that Spermidine (SPD) significantly increased protein expression of autophagy markers microtubule-associated protein 1 light chain 3 beta-II (MAP1LC3B-II/LC3B-II) and sequestosome-1/p62 (SQSTM1/p62), and evoked autophagic flux in FGSCs. Moreover, SPD increased the number and viability of FGSCs in vitro. Further, we found that SPD significantly reduced basal or hydrogen peroxide (H2O2)-induced up-regulated protein expression of the aging markers, cyclin dependent kinase inhibitor 2A (p16/CDKN2A) and tumor protein 53 (p53). After knockdown of p62 in FGSCs, p16 protein levels were significant higher compared with controls. However, protein p16 levels were not significantly changed in p62 knockdown FGSCs with SPD treatment compared with without SPD. Moreover, SPD significantly changed the expression of autophagy-related genes and pathways in FGSCs, as shown by bioinformatics analysis of RNA sequencing data. Additionally, SPD significantly inhibited AKT/mTOR phosphorylation.
    CONCLUSIONS: SPD induces cytoprotective autophagy in FGSCs in vitro and ameliorates cellular senescence of FGSCs induced by H2O2. Furthermore, SPD can ameliorate cellular senescence of FGSCs through p62. SPD might induce autophagy in FGSCs via the PI3K/Akt pathway. Our findings could be helpful for delaying aging of female germ cells due to oxidative stress and preserving female fertility.
    Keywords:  Anti- oxidative stress; Anti-aging; Autophagy; Female germline stem cells; Spermidine; p62
    DOI:  https://doi.org/10.1186/s13578-021-00614-4
  4. Oncogene. 2021 Jun 09.
      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.
    DOI:  https://doi.org/10.1038/s41388-021-01862-x
  5. Front Cell Dev Biol. 2021 ;9 658861
      Colorectal cancer is the leading cause of death from cancer globally. The current treatment protocol still heavily relies on early detection and surgery. The molecular mechanisms underlying development of colorectal cancer are clinically important and determine the prognosis and treatment response. The arginine metabolism pathway is hyperactive in colorectal cancer and several molecules involved in the pathway are potential targets for chemoprevention and targeted colorectal cancer therapy. Endothelial nitric oxide synthase (eNOS), argininosuccinate synthetase and ornithine decarboxylase (ODC) are the main enzymes for arginine metabolism. Limiting arginine-rich meat consumption and inhibiting ODC activity largely reduces polyamine synthesis and the incidence of colorectal cancer. Arginine transporter CAT-1 and Human member 14 of the solute carrier family 6 (SLC6A14) are overexpressed in colorectal cancer cells and contributes to intracellular arginine levels. Human member 9 of the solute carrier family 38 (SLC38A9) serves as a component of the lysosomal arginine-sensing machinery. Pharmaceutical inhibition of single enzyme or arginine transporter is hard to meet requirement of restoring of abnormal arginine metabolic network. Apart from application in early screening for colorectal cancer, microRNA-based therapeutic strategy that simultaneously manipulating multiple targets involved in arginine metabolism brings promising future in the treatment of colorectal cancer.
    Keywords:  arginine metabolism; colorectal cancer; signal pathway; stem cells; transporters protein
    DOI:  https://doi.org/10.3389/fcell.2021.658861
  6. Plant Direct. 2021 May;5(5): e00329
      Traditional breeding and molecular approaches have been used to develop tobacco varieties with reduced nicotine and secondary alkaloid levels. However, available low-alkaloid tobacco varieties have impaired leaf quality likely due to the metabolic consequences of nicotine biosynthesis downregulation. Recently, we found evidence that the unbalanced crosstalk between nicotine and polyamine pathways is involved in impaired leaf ripening of a low-alkaloid (LA) Burley 21 line having a mutation at the Nic1 and Nic2 loci, key biosynthetic regulators of nicotine biosynthesis. Since the Nic1 and Nic2 loci are comprised of several genes, all phenotypic changes seen in LA Burley 21 could be due to a mixture of genetics-based responses. Here, we investigated the commercial burley variety TN90 LC and its transgenic versions with only one downregulated gene, either putrescine methyl transferase (PMT-RNAi) or PR50-protein (PR50-RNAi). Nicotine levels of cured lamina of TN90 LC, TN90 PMT-RNAi and TN90 PR50-RNAi, were 70.5 ± 3.8, 2.4 ± 0.5, and 6.0 ± 1.1 mg/g dry weight, respectively. Low-alkaloid transgenic lines showed delayed leaf maturation and impaired leaf quality. We analyzed polyamine contents and ripening markers in wild-type TN90 control plants (WT) and the two transgenic lines. The ripening markers revealed that the PMT-RNAi line showed the most pronounced impaired leaf maturation phenotype at harvest, characterized by higher chlorophyll (19%) and glucose (173%) contents and more leaf mesophyll cells per area (25%), while the ripening markers revealed that maturation of PR50-RNAi plants was intermediate between PMT-RNAi and WT lines. Comparative polyamine analyses showed an increase in free and conjugated polyamines in roots of both transgenic lines, this being most pronounced in the PMT-RNAi plants. For PMT-RNAi plants, there were further perturbations of polyamine content in the leaves, which mirrored the general phenotype, as PR50-RNAi transgenic plants looked more similar to the WT than PMT-RNAi transgenic plants. Activity of ornithine decarboxylase, the enzyme that catalyzes the committing step of polyamine biosynthesis, was significantly higher in roots and mature leaves of PMT-RNAi plants in comparison to WT, while there was no increase observed for arginine decarboxylase. Treatment of both transgenic lines with polyamine biosynthesis inhibitors decreased the polyamine content and ameliorated the phenotype, confirming the intricate interplay of polyamine and nicotine biosynthesis in tobacco and the influence of this interplay on leaf ripening.
    Keywords:  PR50; inhibition of nicotine biosynthesis; ornithine decarboxylase; polyamines; putrescine methyl transferase; ripening markers
    DOI:  https://doi.org/10.1002/pld3.329
  7. Plant Physiol Biochem. 2021 May 26. pii: S0981-9428(21)00278-3. [Epub ahead of print]166 41-52
      Polyamines (PA) have multifarious roles in plant-environment interaction and stress responses. In conjunction with GABA shunt, they regulate induction of tolerance under salinity stress in plants. Here, we tested the hypothesis that silicon improves salt tolerance through mediating vital metabolic pathways rather than acting as a mere mechanical barrier. Seedlings of two rice (Oryza sativa L.) cultivars MTU 1010 (salt-sensitive) & Nonabokra (salt-tolerant) growing in hydroponic culture were treated with NaCl (0, 25, 50 & 100 mM) combined with or without Si (2 mM). NaCl stress enhanced PA synthesizing enzymes activity and PA production in salt tolerant cultivar Nonabokra, whereas in the sensitive cultivar, MTU 1010 both declined. Enhanced activities of GABA synthesizing enzymes along with a decline in the activities of GABA degrading enzymes under NaCl exposure led to GABA accumulation in both the cultivars. The interactive effects of silicon and NaCl also induced the activities of the enzymes related to polyamine biosynthesis and inhibited polyamine degrading enzymes that enhanced PA contents in the cultivars. Supplemental Si decreased endogenous GABA levels by modulating GABA metabolising enzymes under NaCl stress. On the basis of all tested parameters cv. MTU 1010 was proven to be more responsive towards silicon application than cv. Nonabokra. Such study of silicon-induced polyamine accretion and reduced GABA accumulation may lower oxidative damage in rice cultivars under NaCl stress and thereby form a successful strategy to boost tolerance.
    Keywords:  Amelioration; GABA shunt; Polyamine; ROS; Rice; Salinity; Silicon
    DOI:  https://doi.org/10.1016/j.plaphy.2021.05.030
  8. Physiol Plant. 2021 Jun 09.
      Polyamines (PAs) play important roles in plant defense against pathogens, but the regulation of PA metabolism by hormone-mediated defense signaling pathways has not been studied in depth. In this study, the modulation of PA metabolism by salicylic acid (SA) was analyzed in Arabidopsis by combining the exogenous application of this hormone with PA biosynthesis and SA synthesis/signaling mutants. SA induced notable modifications of PA metabolism, mainly consisting in putrescine (Put) accumulation both in whole-plant extracts and apoplastic fluids. Put was accumulated at the expense of increased biosynthesis by Arginine Decarboxylase 2 and decreased oxidation by Copper Amine Oxidase. Enhancement of Put levels by SA was independent of the regulatory protein Non-Expressor of Pathogenesis Related Genes 1 (NPR1) and the signaling kinases MKK4 and MPK3, but depended on MPK6. However, plant infection by Pseudomonas syringae pv. tomato DC3000 elicited Put accumulation in an SA-dependent way. The present study demonstrates a clear connection between SA signaling and plant PA metabolism in Arabidopsis and contributes to understanding the mechanisms by which SA modulates PA levels during plant-pathogen interactions. This article is protected by copyright. All rights reserved.
    Keywords:  Apoplast; Arginine decarboxylase; MAPK; NPR1; Plant-pathogen interactions; Polyamines; Pseudomonas syringae; Putrescine; salicylic acid
    DOI:  https://doi.org/10.1111/ppl.13478
  9. J Chromatogr A. 2021 May 24. pii: S0021-9673(21)00402-7. [Epub ahead of print]1651 462278
      A simple method for the determination of polyamines and their N-acetylated forms was developed using benzoyl chloride as derivatization reagent, and 1,6-diaminohexane as internal standard, followed by liquid-liquid extraction with ethyl acetate. The organic extract was injected in a gas chromatograph using a programmed temperature vaporizer and the determination and quantification was performed with a quadrupole mass spectrometer. There was no matrix effect with the proposed method, so internal calibration was used to quantify the corresponding derivatives. Good linear responses were obtained in the range from the limits of detection to 500 µg L-1 (50 µg L-1 for spermidine), with correlation coefficients varying from 0.9591 to 0.9968. The limits of quantification (S/N = 10) ranged 1.0 - 8.3 µg L-1. Recoveries were found between 82 - 117%, showing the good accuracy of the proposed method. Intra- and inter-day precision assays, expressed as relative standard deviation (RSD) were evaluated at two different concentration levels (low and high), showing values in the range of 2.4 - 6.1% and 5.2 - 9.0% for repeatability and reproducibility, respectively (6.9 - 9.7% and 14.1 - 14.6% for spermidine). Successful determination of the studied polyamines and their N-acetylated forms was performed on the saliva of 17 volunteers.
    Keywords:  Benzoyl chloride derivatization; Gas chromatography-mass spectrometry; Polyamines; Saliva samples
    DOI:  https://doi.org/10.1016/j.chroma.2021.462278
  10. Eur J Med Chem. 2021 May 28. pii: S0223-5234(21)00435-9. [Epub ahead of print]222 113586
      The aim of this study was to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. Indeed, it is well-known that polyamine transport system is upregulated in tumor cells. 3',4,4',5'-tetramethoxychalcone was selected as parent chalcone since it was found to be an efficient anti-proliferative agent on various cancer cells. A series of five chalcone-polyamine conjugates was obtained using the 4-bromopropyloxy-3',4',5'-trimethoxychalcone as a key intermediate. Chalcone core and polyamine tails were fused through an amine bond. These conjugates were found to possess a marked in vitro antiproliferative effect against colorectal (HT-29 and HCT-116) and prostate cancer (PC-3 and DU-145) cell lines. The most active conjugate (compound 8b) was then chosen for further biological evaluations to elucidate mechanisms responsible for its antiproliferative activity. Investigations on cell cycle distribution revealed that this conjugate can prevent the proliferation of human colorectal and prostate cancer cells by blocking the cell cycle at the G1 and G2 phase, respectively. Flow cytometry analysis revealed a sub-G1 peak, characteristic of apoptotic cell population and our inquiries highlighted apoptosis induction at early and later stages through several pro-apoptotic markers. Therefore, this chalcone-N1-spermidine conjugate could be considered as a promising agent for colon and prostatic cancer adjuvant therapy.
    Keywords:  Anti-proliferative activity; Apoptosis; Cell cycle arrest; Chalcone polyamine conjugates; Colorectal and prostate cancer; Polyamine-vectorized anticancer drugs
    DOI:  https://doi.org/10.1016/j.ejmech.2021.113586
  11. FEBS Lett. 2021 Jun 10.
      Decoding of ornithine decarboxylase (ODC) antizyme 1 (OAZ1) mRNA, which harbours two open reading frames (ORF1 and ORF2) interrupted by a naturally occurring Premature Termination Codon (PTC), produces an 8 kDa truncated polypeptide termed Orf1p, unless the PTC is bypassed by +1 ribosomal frameshifting. In this study, we identified Orf1p as an endogenous ubiquitin-dependent substrate of the 26S proteasome both in yeast and mammalian cells. Surprisingly, we found that the ribosome-associated quality control factor Rqc1 and the ubiquitin ligase Ltn1 are critical for Orf1p degradation. In addition, the cytosolic protein quality control chaperone system Hsp70/Hsp90 and their corresponding co-chaperones Sse1, Fes1, Sti1, and Cpr7 are also required for Orf1p proteolysis. Our study finds that Orf1p, which is naturally synthesized as a result of a premature translation termination event, requires the coordinated role of both ribosome-associated and cytosolic protein quality control factors for its degradation.
    Keywords:  Antizyme; Ubiquitin/Proteasome System (UPS); protein degradation; ribosomal frameshifting; ribosome-associated protein quality control (RQC)
    DOI:  https://doi.org/10.1002/1873-3468.14147