bims-polyam Biomed News
on Polyamines
Issue of 2020‒09‒20
six papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology

  1. Eur J Immunol. 2020 Sep 18.
    O'Brien KL, Assmann N, O'Connor E, Keane C, Walls J, Choi C, Oefner PJ, Gardiner CM, Dettmer K, Finlay DK.
      Cellular metabolism is dynamically regulated in Natural Killer (NK) cells and strongly influences their responses. Metabolic dysfunction is linked to defective NK cell responses in diseases such as obesity and cancer. The transcription factors, sterol regulatory element binding protein (SREBP) and cMyc are crucial for controlling NK cell metabolic and functional responses, though the mechanisms involved are not fully understood. This study reveals a new role for SREBP in NK cells in supporting de novo polyamine synthesis through facilitating elevated cMyc expression. Polyamines have diverse roles and their de novo synthesis is required for NK cell glycolytic and oxidative metabolism and to support optimal NK cell effector functions. When NK cells with impaired SREBP activity were supplemented with exogenous polyamines, NK cell metabolic defects were not rescued but these NK cells displayed significant improvement in some effector functions. One role for polyamines is in the control of protein translation where spermidine supports the posttranslational hypusination of translation factor eIF5a. Pharmacological inhibition of hypusination also impacts upon NK cell metabolism and effector function. Considering recent evidence that cholesterol-rich tumour microenvironments inhibit SREBP activation and drive lymphocyte dysfunction, this study provides key mechanistic insight into this tumour-evasion strategy. This article is protected by copyright. All rights reserved.
    Keywords:  SREBP; cMyc; metabolism; natural killer cell; polyamines
  2. Arch Biochem Biophys. 2020 Sep 15. pii: S0003-9861(20)30596-8. [Epub ahead of print] 108587
    Nakamura A, Takahashi D, Nakamura Y, Yamada T, Matsumoto M, Hase K.
      Polyamines produced by both prokaryotes and eukaryotes are bioactive substances with pleiotropic effects. Accumulating evidence has demonstrated that polyamines contribute to anti-inflammatory responses by suppressing the expression of proinflammatory cytokines in mononuclear cells and macrophages. However, the effects of polyamines on CD4+ T cell responses remain to be elucidated. Here, we investigated the effect of polyamines on cell fate decisions of naïve CD4+ T cells in vitro. We found that endogenously generated polyamines are essential for the development of T helper 2 (Th2) cells. Treatment with DL-2-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, diminished GATA3 expression in CD4+ T cells under Th2-skewed conditions. Supplementation of exogenous polyamines rescued GATA3 downregulation caused by DFMO treatment in CD4+ T cells. Transcriptome analysis revealed that deprivation of endogenous polyamines resulted in upregulated Th9-related genes, such as Il9, Irf4, and Batf3, even under the Th2-skewing conditions. Depletion of intracellular polyamines reduced GATA3 expression but increased IL-9-producing CD4+ T cells under both Th2 and Th9-skewing conditions. Furthermore, oral administration of DFMO increased IL-9-producing CD4+ T cells in small intestine in mice. Thus, our data indicate that polyamines play a critical role in the regulation of the Th2/Th9 balance.
    Keywords:  Differentiation; GATA3; Polyamines; Th2; Th9
  3. Oncol Lett. 2020 Nov;20(5): 138
    Telang N.
      Negative growth regulatory tumor suppressor genes and positive growth regulatory oncogenes serve important roles in initiation/progression of colon cancer. Germline mutation in the adenomatous polyposis coli (APC) tumor suppressor gene represents a primary genetic defect for familial adenomatous polyposis (FAP) syndrome, a predisposing factor for clinical colon cancer. Somatic mutations in the APC gene are common in sporadic colon cancer. Preclinical and clinical efficacy is documented for targeted therapy with non-steroidal anti-inflammatory drugs, selective cyclo-oxygenase-2 inhibitors for prostaglandin biosynthesis and selective inhibitor of ornithine decarboxylase for polyamine biosynthesis. However, these therapeutic options lead to systemic toxicity, acquired tumor resistance and emergence of therapy resistant cancer stem cells. By contrast, non-toxic natural products are unlikely to exhibit drug resistance and may represent testable alternatives for therapy resistant colon cancer. Tumorigenic Apc [-/-] colonic epithelial cell lines derived from preclinical FAP models provide novel cellular models for drug resistant cancer stem cells. Apc [-/-] Sulindac resistant (SUL-R) cells exhibit upregulated expression levels of cancer stem cell markers. Natural products, such as naturally occurring vitamin A derivative all-trans retinoic acid (ATRA) and the anti-cancer agent from Turmeric root curcumin (CUR), represent testable alternatives. Relative to the non-tumorigenic Apc [+/+] C57 COL colonic epithelial cells, the tumorigenic Apc [-/-] 1638N COL and Apc [-/-] 850 MIN COL cells exhibit aneuploid cell hyper-proliferation and upregulated expression of Apc target genes β-catenin, cyclin D1, c-myc and COX-2. The SUL-R phenotypes exhibit enhanced tumor spheroid formation and upregulated expression levels of stem cell markers CD44, CD133 and c-Myc. Treatment of the SUL-R stem cells with ATRA and CUR inhibits tumor spheroid formation and reduces the expression of stem cell markers. Stem cell models developed for FAP syndrome provide a novel experimental approach to identify mechanistic leads for efficacious natural products as testable alternatives for therapy-resistant, genetically predisposed colon cancer.
    Keywords:  adenomatous polyposis coli; drug resistance; stem cells
  4. Ecotoxicol Environ Saf. 2020 Sep 10. pii: S0147-6513(20)31103-9. [Epub ahead of print]207 111265
    Jiang D, Hou J, Gao W, Tong X, Li M, Chu X, Chen G.
      Aluminum (Al) toxicity is a major yield-limiting factor for crops in acidic soils. In this work, we have investigated the potential role of spermidine (Spd) on Al toxicity in rice chloroplasts. Exogenous Spd markedly reduced Al concentration and elevated other nutrient elements such as Mn, Mg, Fe, K, Ca, and Mo in chloroplasts of Al-treated plants. Meanwhile, Spd further activated arginine decarboxylase (ADC) activity of key enzyme in polyamine (PA) synthesis, and enhanced PA contents in chloroplasts. Spd application dramatically addressed Al-induced chlorophyll (Chl) losses, inhibited thylakoid membrane protein complexes degradation, especially photosystem II (PSII), and significantly depressed the accumulations of superoxide radical (O2·-), hydrogen peroxide (H2O2), and malondialdehyde (MDA) in chloroplasts. Spd addition activated antioxidant enzyme activities and decreased soluble sugar content in chloroplasts compared with Al treatment alone. Spd not only reversed the inhibition of photosynthesis-related gene transcript levels induced by Al toxicity, but diminished the increased expression of Chl catabolism-related genes. Furthermore, Chl fluorescence analysis showed that Spd protected PSII reaction centers and photosynthetic electron transport chain under Al stress, thus improving photosynthetic performance. These results suggest that PAs are involved in Al tolerance in rice chloroplasts and can effectively protect the integrity and function of photosynthetic apparatus, especially PSII, by mitigating oxidative damage induced by Al toxicity.
    Keywords:  Aluminum; Chloroplast; Nutrient elements; Oxidative stress; Spermidine
  5. Physiol Mol Biol Plants. 2020 Sep;26(9): 1815-1829
    Rathinapriya P, Pandian S, Rakkammal K, Balasangeetha M, Alexpandi R, Satish L, Rameshkumar R, Ramesh M.
      Abstract: Soil salinity is a major abiotic stress that adversely affects crop growth, development and productivity worldwide. In this study, the individual and synergistic roles of putrescine (Put) and spermidine (Spd) in salinity stress tolerance of foxtail millet (Setaria italica L.) was assessed. In the present study, plants treated with combined biogenic amines Put + Spd possess very efficient antioxidant enzyme systems which help to control the uninhibited oxidation and protect the plants from oxidative damage by ROS scavenging. Additionally, lower concentration of Put + Spd under NaCl stress showed reduced hydrogen peroxide, electrolyte leakage and caspase-like activity than control. FTIR analysis underlying the ability of PAs induced tolerance and the chemical bonds of Put + Spd treated plants were reminiscent of control plants. Moreover, histochemical analysis with 2',7'-dichlorofluorescein diacetate (DCF-DA), 3,3'-Diaminobenzidine (DAB) and nitrotetrazolium blue chloride (NBT) revealed that ROS accumulation was inhibited by combined PAs under salt stress condition. These results showed that Put + Spd significantly improve the endogenous PAs, which enhance high-salinity stress tolerance by detoxifying ROS. For the first time, the synergistic ROS scavenging ability of Put along with Spd was investigated upon salinity tolerance in C4 model foxtail millet crop. Overall, our findings illustrated the implication for improving salinity tolerance of agronomically important crop species.Graphic abstract:
    Keywords:  Confocal laser scanning microscope; Fourier transform-infrared spectroscopy; Histochemical analysis; Polyamines; Reactive oxygen species; Salinity stress
  6. Nat Microbiol. 2020 Sep 14.
    Rocha RO, Elowsky C, Pham NTT, Wilson RA.
      Cellular adhesion mediates many important plant-microbe interactions. In the devastating blast fungus Magnaporthe oryzae1, powerful glycoprotein-rich mucilage adhesives2 cement melanized and pressurized dome-shaped infection cells-appressoria-to host rice leaf surfaces. Enormous internal turgor pressure is directed onto a penetration peg emerging from the unmelanized, thin-walled pore at the appressorial base1-4, forcing it through the leaf cuticle where it elongates invasive hyphae in underlying epidermal cells5. Mucilage sealing around the appressorial pore facilitates turgor build-up2, but the molecular underpinnings of mucilage secretion and appressorial adhesion are unknown. Here, we discovered an unanticipated and sole role for spermine in facilitating mucilage production by mitigating endoplasmic reticulum (ER) stress in the developing appressorium. Mutant strains lacking the spermine synthase-encoding gene SPS1 progressed through all stages of appressorial development, including penetration peg formation, but cuticle penetration was unsuccessful due to reduced appressorial adhesion, which led to solute leakage. Mechanistically, spermine neutralized off-target oxygen free radicals produced by NADPH oxidase-1 (Nox1)3,6 that otherwise elicited ER stress and the unfolded protein response, thereby critically reducing mucilage secretion. Our study reveals that spermine metabolism via redox buffering of the ER underpins appressorial adhesion and rice cell invasion and provides insights into a process that is fundamental to host plant infection.