bims-polyam 2021-09-19 papers

Issue of 2021–09–19
four papers selected by
Sebastian J. Hofer, University of Graz

Elife. 2021 09 14. pii: e69269. [Epub ahead of print]10

Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function.

Sonia Coni, Federica A Falconio, Marta Marzullo, Marzia Munafò, Benedetta Zuliani, Federica Mosti, Alessandro Fatica, Zaira Ianniello, Rosa Bordone, Alberto Macone, Enzo Agostinelli, Alessia Perna, Tanja Matkovic, Stephan Sigrist, Gabriella Silvestri, Gianluca Canettieri, Laura Ciapponi.

Microsatellite expansions of CCTG repeats in the cellular nucleic acid-binding protein (CNBP) gene leads to accumulation of toxic RNA and have been associated with myotonic dystrophy type 2 (DM2). However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA-binding protein that regulates translation and is required for mammalian development. Here, we show that depletion of Drosophila CNBP in muscles causes ageing-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion. Of note, we show a reduction of the CNBP-polyamine axis in muscles from DM2 patients. Mechanistically, we provide evidence that dCNBP controls polyamine metabolism through binding dOdc mRNA and regulating its translation. Remarkably, the locomotor defect of dCNBP-deficient flies is rescued by either polyamine supplementation or dOdc1 overexpression. We suggest that this dCNBP function is evolutionarily conserved in vertebrates with relevant implications for CNBP-related pathophysiological conditions.

Keywords: CNBP; D. melanogaster; Drosophila melanogaster; ODC; genetics; genomics; human; myotonic dystrophy 2; neuroscience; polyamine; translation

DOI: https://doi.org/10.7554/eLife.69269

Aging (Albany NY). 2021 Sep 13. 13(undefined):

Circulating acetylated polyamines correlate with Covid-19 severity in cancer patients.

Mélanie Bourgin, Lisa Derosa, Carolina Alves Costa Silva, Anne-Gaëlle Goubet, Agathe Dubuisson, François-Xavier Danlos, Claudia Grajeda-Iglesias, Luigi Cerbone, Arthur Geraud, Ariane Laparra, Fanny Aprahamian, Nitharsshini Nirmalathasan, Frank Madeo, Laurence Zitvogel, Guido Kroemer, Sylvère Durand.

Cancer patients are particularly susceptible to the development of severe Covid-19, prompting us to investigate the serum metabolome of 204 cancer patients enrolled in the ONCOVID trial. We previously described that the immunosuppressive tryptophan/kynurenine metabolite anthranilic acid correlates with poor prognosis in non-cancer patients. In cancer patients, we observed an elevation of anthranilic acid at baseline (without Covid-19 diagnosis) and no further increase with mild or severe Covid-19. We found that, in cancer patients, Covid-19 severity was associated with the depletion of two bacterial metabolites, indole-3-proprionate and 3-phenylproprionate, that both positively correlated with the levels of several inflammatory cytokines. Most importantly, we observed that the levels of acetylated polyamines (in particular N1-acetylspermidine, N1,N8-diacetylspermidine and N1,N12-diacetylspermine), alone or in aggregate, were elevated in severe Covid-19 cancer patients requiring hospitalization as compared to uninfected cancer patients or cancer patients with mild Covid-19. N1-acetylspermidine and N1,N8-diacetylspermidine were also increased in patients exhibiting prolonged viral shedding (>40 days). An abundant literature indicates that such acetylated polyamines increase in the serum from patients with cancer, cardiovascular disease or neurodegeneration, associated with poor prognosis. Our present work supports the contention that acetylated polyamines are associated with severe Covid-19, both in the general population and in patients with malignant disease. Severe Covid-19 is characterized by a specific metabolomic signature suggestive of the overactivation of spermine/spermidine N1-acetyl transferase-1 (SAT1), which catalyzes the first step of polyamine catabolism.

Keywords: COVID-19; cancer; metabolomics; microbiota; polyamines

DOI: https://doi.org/10.18632/aging.203525

Breast Cancer Res Treat. 2021 Sep 16.

Hyperglycemic conditions proliferate triple negative breast cancer cells: role of ornithine decarboxylase.

Caleb C Capellen, Jose Ortega-Rodas, M Jane Morwitzer, Hadassha M N Tofilau, Matthew Dunworth, Robert A Casero, Surabhi Chandra.

PURPOSE: Several cancer subtypes (pancreatic, breast, liver, and colorectal) rapidly advance to higher aggressive stages in diabetes. Though hyperglycemia has been considered as a fuel for growth of cancer cells, pathways leading to this condition are still under investigation. Cellular polyamines can modulate normal and cancer cell growth, and inhibitors of polyamine synthesis have been approved for treating colon cancer, however the role of polyamines in diabetes-mediated cancer advancement is unclear as yet. We hypothesized that polyamine metabolic pathway is involved with increased proliferation of breast cancer cells under high glucose (HG) conditions.
METHODS: Studies were performed with varying concentrations of glucose (5-25 mM) exposure in invasive, triple negative breast cancer cells, MDA-MB-231; non-invasive, estrogen/progesterone receptor positive breast cancer cells, MCF-7; and non-tumorigenic mammary epithelial cells, MCF-10A.
RESULTS: There was a significant increase in proliferation with HG (25 mM) at 48-72 h in both MDA-MB-231 and MCF-10A cells but no such effect was observed in MCF-7 cells. This was correlated to higher activity of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine synthesis pathway. Inhibitor of polyamine synthesis (difluoromethylornithine, DFMO, 5 mM) was quite effective in suppressing HG-mediated cell proliferation and ODC activity in MDA-MB-231 and MCF-10A cells. Polyamine (putrescine) levels were significantly elevated with HG treatment in MDA-MB-231 cells. HG exposure also increased the metastasis of MDA-MB-231 cells.
CONCLUSIONS: Our cellular findings indicate that polyamine inhibition should be explored in patient population as a target for future chemotherapeutics in diabetic breast cancer.

Keywords: Breast cancer; Diabetes; High glucose; Ornithine decarboxylase; Polyamine; Putrescine

DOI: https://doi.org/10.1007/s10549-021-06388-0

Cancer Gene Ther. 2021 Sep 14.

The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme.

Zuzanna Urban-Wójciuk, Amy Graham, Karen Barker, Colin Kwok, Yordan Sbirkov, Louise Howell, James Campbell, Patrick M Woster, Evon Poon, Kevin Petrie, Louis Chesler.

Deregulated polyamine biosynthesis is emerging as a common feature of neuroblastoma and drugs targeting this metabolic pathway such as DFMO are in clinical and preclinical development. The polyamine analog verlindamycin inhibits the polyamine biosynthesis pathway enzymes SMOX and PAOX, as well as the histone demethylase LSD1. Based on our previous research in acute myeloid leukemia (AML), we reasoned verlindamycin may also unblock neuroblastoma differentiation when combined with all-trans-retinoic acid (ATRA). Indeed, co-treatment with verlindamycin and ATRA strongly induced differentiation regardless of MYCN status, but in MYCN-expressing cells, protein levels were strongly diminished. This process was not transcriptionally regulated but was due to increased degradation of MYCN protein, at least in part via ubiquitin-independent, proteasome-dependent destruction. Here we report that verlindamycin effectively induces the expression of functional tumor suppressor-antizyme via ribosomal frameshifting. Consistent with previous results describing the function of antizyme, we found that verlindamycin treatment led to the selective targeting of ornithine decarboxylase (the rate-limiting enzyme for polyamine biosynthesis) as well as key oncoproteins, such as cyclin D and Aurora A kinase. Retinoid-based multimodal differentiation therapy is one of the few interventions that extends relapse-free survival in MYCN-associated high-risk neuroblastoma and these results point toward the potential use of verlindamycin in this regimen.

DOI: https://doi.org/10.1038/s41417-021-00386-6