bims-polyam 2021-02-21 papers

Issue of 2021–02–21
four papers selected by
Sebastian J. Hofer, University of Graz

J Clin Invest. 2021 Feb 15. pii: 126299. [Epub ahead of print]131(4):

Aberrant AZIN2 and polyamine metabolism precipitates tau neuropathology.

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell's response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer's disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD.

Keywords: Alzheimer disease; Metabolism; Neurological disorders; Neuroscience; Polyamines

DOI: https://doi.org/10.1172/JCI126299

Cancer Biol Ther. 2021 Feb 18. 1-13

Harnessing the polyamine transport system to treat BRAF inhibitor-resistant melanoma.

Eric T Alexander, Olivia El Naggar, Erin Fahey, Kelsey Mariner, Julia Donnelly, Katelyn Wolfgang, Otto Phanstiel, Susan K Gilmour.

BRAF mutations are present in over half of all melanoma tumors. Although BRAF inhibitors significantly improve survival of patients with metastatic melanoma, recurrences occur within several months. We previously reported that BRAF mutant melanoma cells are more sensitive to a novel arylmethyl-polyamine ( AP ) compound that exploits their increased polyamine uptake compared to that of BRAF wildtype cells. Using an animal model of BRAF inhibitor-resistant melanoma, we show that co-treatment with the BRAF inhibitor, PLX4720, and AP significantly delays the recurrence of PLX4720-resistant melanoma tumors and decreases tumor-promoting macrophages. Development of BRAF inhibitor-resistance enriches for metastatic cancer stem cells (CSC) and increases tumor-promoting macrophages. In vitro studies demonstrated that CD304+, CXCR4+ spheroid cultures of BRAF mutant melanoma cells are resistant to PLX4720 but are more sensitive to AP compared to monolayer cultures of the same cells. AP significantly inhibited YUMM1.7 melanoma cell invasiveness across a Matrigel-coated filter using the CXCR4 ligand, SDF-1α, as the chemoattractant. AP also blocked the chemotactic effect of SDF-1α on CXCR4+ macrophages and inhibited M2 polarization of macrophages. In melanoma-macrophage co-cultures, AP prevented the PLX4720-induced release of pro-tumorigenic growth factors, such as VEGF, from macrophages and prevented the macrophage rescue of BRAF mutant melanoma cells treated with PLX4720. Our study offers a novel therapy ( AP ) to treat chemo-resistant melanoma. AP is unique because it targets the polyamine transport system in BRAF inhibitor-resistant CSCs and also blocks CXCR4 signaling in invasive melanoma cells and pro-tumorigenic macrophages.

Keywords: Polyamines; braf inhibition; cxcr4; difluoromethylornithine; transport inhibitor

DOI: https://doi.org/10.1080/15384047.2021.1883185

Sci Adv. 2021 Feb;pii: eabc8929. [Epub ahead of print]7(8):

Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma.

Jason Miska, Aida Rashidi, Catalina Lee-Chang, Peng Gao, Aurora Lopez-Rosas, Peng Zhang, Rachel Burga, Brandyn Castro, Ting Xiao, Yu Han, David Hou, Samay Sampat, Alex Cordero, Joshua S Stoolman, Craig M Horbinski, Mark Burns, Yana K Reshetnyak, Navdeep S Chandel, Maciej S Lesniak.

Glioblastoma is characterized by the robust infiltration of immunosuppressive tumor-associated myeloid cells (TAMCs). It is not fully understood how TAMCs survive in the acidic tumor microenvironment to cause immunosuppression in glioblastoma. Metabolic and RNA-seq analysis of TAMCs revealed that the arginine-ornithine-polyamine axis is up-regulated in glioblastoma TAMCs but not in tumor-infiltrating CD8+ T cells. Active de novo synthesis of highly basic polyamines within TAMCs efficiently buffered low intracellular pH to support the survival of these immunosuppressive cells in the harsh acidic environment of solid tumors. Administration of difluoromethylornithine (DFMO), a clinically approved inhibitor of polyamine generation, enhanced animal survival in immunocompetent mice by causing a tumor-specific reduction of polyamines and decreased intracellular pH in TAMCs. DFMO combination with immunotherapy or radiotherapy further enhanced animal survival. These findings indicate that polyamines are used by glioblastoma TAMCs to maintain normal intracellular pH and cell survival and thus promote immunosuppression during tumor evolution.

DOI: https://doi.org/10.1126/sciadv.abc8929

mSystems. 2021 Feb 16. pii: e01003-20. [Epub ahead of print]6(1):

Production and Excretion of Polyamines To Tolerate High Ammonia, a Case Study on Soil Ammonia-Oxidizing Archaeon "Candidatus Nitrosocosmicus agrestis".

Liangting Liu, Mengfan Liu, Yiming Jiang, Weitie Lin, Jianfei Luo.

Ammonia tolerance is a universal characteristic among the ammonia-oxidizing bacteria (AOB); in contrast, the known species of ammonia-oxidizing archaea (AOA) have been regarded as ammonia sensitive, until the identification of the genus "Candidatus Nitrosocosmicus." However, the mechanism of its ammonia tolerance has not been reported. In this study, the AOA species "Candidatus Nitrosocosmicus agrestis," obtained from agricultural soil, was determined to be able to tolerate high concentrations of NH3 (>1,500 μM). In the genome of this strain, which was recovered from metagenomic data, a full set of genes for the pathways of polysaccharide metabolism, urea hydrolysis, arginine synthesis, and polyamine synthesis was identified. Among them, the genes encoding cytoplasmic carbonic anhydrase (CA) and a potential polyamine transporter (drug/metabolite exporter [DME]) were found to be unique to the genus "Ca. Nitrosocosmicus." When "Ca. Nitrosocosmicus agrestis" was grown with high levels of ammonia, the genes that participate in CO2/HCO3 - conversion, glutamate/glutamine syntheses, arginine synthesis, polyamine synthesis, and polyamine excretion were significantly upregulated, and the polyamines, including putrescine and spermidine, had significant levels of production. Based on genome analysis, gene expression quantification, and polyamine determination, we propose that the production and excretion of polyamines is probably one of the reasons for the ammonia tolerance of "Ca. Nitrosocosmicus agrestis," and even of the genus "Ca. Nitrosocosmicus."IMPORTANCE Ammonia tolerance of AOA is usually much lower than that of the AOB, which makes the AOB rather than AOA a predominant ammonia oxidizer in agricultural soils, contributing to global N2O emission. Recently, some AOA species from the genus "Ca. Nitrosocosmicus" were also found to have high ammonia tolerance. However, the reported mechanism for the ammonia tolerance is very rare and indeterminate for AOB and for AOA species. In this study, an ammonia-tolerant AOA strain of the species "Ca. Nitrosocosmicus agrestis" was identified and its potential mechanisms for ammonia tolerance were explored. This study will be of benefit for determining more of the ecological role of AOA in agricultural soils or other environments.

Keywords: Nitrosocosmicus; ammonia tolerance; ammonia-oxidizing archaea; polyamines

DOI: https://doi.org/10.1128/mSystems.01003-20