bims-polyam 2020-03-08 papers

on Polyamines

Issue of 2020–03–08
eight papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy.
Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase.
Polyamine Analogues of Propanediamine Series Inhibit Prostate Tumor Cell Growth and Activate the Polyamine Catabolic Pathway.
The polyamine putrescine promotes human epidermal melanogenesis.
Prevention of multiple system atrophy using human bone marrow-derived mesenchymal stem cells by reducing polyamine and cholesterol-induced neural damages.
Basic Hallmarks of Urothelial Cancer Unleashed in Primary Uroepithelium by Interference with the Epigenetic Master Regulator ODC1.
Proline Biosynthesis Enzyme Genes Confer Salt Tolerance to Switchgrass (Panicum virgatum L.) in Cooperation With Polyamines Metabolism.
Exogenous Spermidine Promotes γ-Aminobutyric Acid Accumulation and Alleviates the Negative Effect of NaCl Stress in Germinating Soybean (Glycine max L.).

J Biol Chem. 2020 Mar 05. pii: jbc.RA119.012376. [Epub ahead of print]

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy.

Renee C Geck, Jackson R Foley, Tracy Murray Stewart, John M Asara, Robert A Casero, Alex Toker.

  Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was due to a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator, antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced, preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.

Keywords:  DNA damage; amino acid; antizyme; breast cancer; difluoromethylornithine; metabolomics; ornithine decarboxylase (ODC); polyamine; triple-negative breast cancer (TNBC)

DOI:  https://doi.org/10.1074/jbc.RA119.012376
J Med Chem. 2020 Mar 06.

Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase.

Yuta Tanaka, Osamu Kurasawa, Akihiro Yokota, Michael G Klein, Koji Ono, Bunnai Saito, Shigemitsu Matsumoto, Masanori Okaniwa, Geza Ambrus-Aikelin, Daisuke Morishita, Satoshi Kitazawa, Noriko Uchiyama, Kazumasa Ogawa, Hiromichi Kimura, Shinichi Imamura.

Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition of DHPS is a promising therapeutic option for the treatment of cancer. To discover novel lead compounds that target DHPS, we conducted synthetic studies with a hit obtained via high-throughput screening. Optimization of the ring structures of the amide compound (2) led to bromobenzothiophene (11g) with potent inhibitory activity against DHPS. X-ray crystallographic analysis of 11g complexed with DHPS revealed a dramatic conformational change in DHPS, which suggests the presence of a novel allosteric site. These findings provide the basis for the development of novel therapy distinct from spermidine mimetic inhibitors.

DOI: https://doi.org/10.1021/acs.jmedchem.9b01979
Anticancer Res. 2020 Mar;40(3): 1437-1441

Polyamine Analogues of Propanediamine Series Inhibit Prostate Tumor Cell Growth and Activate the Polyamine Catabolic Pathway.

Maria V Ploskonos, Sergey P Syatkin, Ekaterina V Neborak, Abdullah Hilal, Kristina Y Sungrapova, Roman I Sokuyev, Mikhail L Blagonravov, Anna Y Korshunova, Alexander A Terentyev.

   BACKGROUND/AIM: Polyamines are important for the growth of eukaryotic cells. At high levels, they promote proliferation, invasion and migration of tumour cells. Polyamine metabolism is an important new target for anticancer therapy. Some polyamine analogues can have an inhibitory effect on tumour cells. The aim of this study was to explore the potential of certain butylated derivatives of propanediamine for prostate cancer chemotherapy.
MATERIALS AND METHODS: Human prostate cancer cells, LNCaP, were used for the evaluation of the antiproliferative activity of polyamine analogs and their influence on spermine oxidase.
RESULTS: Tetrabutyl propanediamine and two new polyamine analogues inhibited the growth of LNCaP cells. At the same time, a strong activation of spermine oxidase was observed.
CONCLUSION: The investigated compounds demonstrated their potential value in the therapy of human prostate cancer. Their effect might be attributed to the activation of the polyamine catabolic pathway.

Keywords:  Polyamines; polyamine analogues; polyamine oxidase; tumour

DOI:  https://doi.org/10.21873/anticanres.14085
J Invest Dermatol. 2020 Feb 28. pii: S0022-202X(20)30219-0. [Epub ahead of print]

The polyamine putrescine promotes human epidermal melanogenesis.

Aishwarya Sridharan, Meng Shi, Vonny Ivon Leo, Nagavidya Subramaniam, Thiam Chye Lim, Takeshi Uemura, Kazuei Igarashi, Steven Thng Tien Guan, Nguan Soon Tan, Leah A Vardy.

  Hyper-pigmentary conditions can arise when melanogenesis in the epidermis is mis-regulated. Understanding the pathways underlying melanogenesis is essential for the development of effective treatments. Here, we show that a group of metabolites called polyamines are important in the control of melanogenesis in human skin. Polyamines are cationic molecules present in all cells and are essential for cellular function. We show that polyamine regulator ODC1 is upregulated in melanocytes from melasma lesional skin. We show that the polyamine putrescine can promote pigmentation in human skin explants and primary melanocytes (NHEM) through induction of Tyrosinase which is rate limiting for the synthesis of melanin. Putrescine supplementation on NHEMs results in activation of polyamine catabolism which results in increased intracellular H202. Polyamine catabolism is also increased in human skin explants that have been treated with putrescine. We further show that inhibition of polyamine catabolism prevents putrescine induced promotion of Tyrosinase levels and pigmentation in NHEMs showing that polyamine catabolism is responsible for the putrescine induction of melanogenesis. Our data showing that putrescine promotes pigmentation has important consequences for hyper- and hypo-pigmented conditions. Further understanding of how polyamines control epidermal pigmentation could open the door for the development of new therapeutics.

Keywords:  Polyamines; epidermis; melanogenesis; pigmentation

DOI:  https://doi.org/10.1016/j.jid.2020.02.009
Stem Cell Res Ther. 2020 Mar 04. 11(1): 63

Prevention of multiple system atrophy using human bone marrow-derived mesenchymal stem cells by reducing polyamine and cholesterol-induced neural damages.

Kyung-Ran Park, Chul Ju Hwang, Hyung-Mun Yun, In Jun Yeo, Dong-Young Choi, Pil-Hoon Park, Hyung Sook Kim, Jung Tae Lee, Young Suk Jung, Sang-Bae Han, Jin Tae Hong.

   BACKGROUND: Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder of unknown etiology, but is closely associated with damage to dopaminergic neurons. MSA progression is rapid. Hence, long-term drug treatments do not have any therapeutic benefits. We assessed the inhibitory effect of mesenchymal stem cells (MSCs) on double-toxin-induced dopaminergic neurodegenerative MSA.
RESULTS: Behavioral disorder was significantly improved and neurodegeneration was prevented following MSC transplantation. Proteomics revealed lower expression of polyamine modulating factor-binding protein 1 (PMFBP1) and higher expression of 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMGCL), but these changes were reversed after MSC transplantation. In the in vitro study, the 6-OHDA-induced effects were reversed following co-culture with MSC. However, PMFBP1 knockdown inhibited the recovery effect due to the MSCs. Furthermore, HMGCL expression was decreased following co-culture with MSCs, but treatment with recombinant HMGCL protein inhibited the recovery effects due to MSCs.
CONCLUSIONS: These data indicate that MSCs protected against neuronal loss in MSA by reducing polyamine- and cholesterol-induced neural damage.

Keywords:  Cholesterol; MSC; Multiple system atrophy (MSA); Polyamines

DOI:  https://doi.org/10.1186/s13287-020-01590-1
Sci Rep. 2020 Mar 02. 10(1): 3808

Basic Hallmarks of Urothelial Cancer Unleashed in Primary Uroepithelium by Interference with the Epigenetic Master Regulator ODC1.

Lars Erichsen, Hans-Helge Seifert, Wolfgang A Schulz, Michèle J Hoffmann, Günter Niegisch, Marcos J Araúzo-Bravo, Marcelo L Bendhack, Cedric Poyet, Thomas Hermanns, Agnes Beermann, Mohamed Hassan, Lisa Theis, Wardah Mahmood, Simeon Santourlidis.

Urothelial carcinoma (UC) is a common disease causing significant morbidity and mortality as well as considerable costs for health systems. Extensive aberrant methylation of DNA is broadly documented in early UC, contributing to genetic instability, altered gene expression and tumor progression. However the triggers initiating aberrant methylation are unknown. Recently we discovered that several genes encoding key enzymes of methyl group and polyamine metabolism, including Ornithine Decarboxylase 1 (ODC1), are affected by DNA methylation in early stage UC. In this study, we investigated the hypothesis that these epigenetic alterations act in a feed-forward fashion to promote aberrant DNA methylation in UC. We demonstrate that siRNA-mediated knockdown of ODC1 expression elicits genome-wide LINE-1 demethylation, induction of LINE-1 transcripts and double-strand DNA breaks and decreases viability in primary cultured uroepithelial cells. Similarly, following siRNA-mediated knockdown of ODC1, UC cells undergo double-strand DNA breaks and apoptosis. Collectively, our findings provide evidence that ODC1 gene hypermethylation could be a starting point for the onset of genome-wide epigenetic aberrations in urothelial carcinogenesis. Furthermore, LINE-1 induction enabled by ODC1 interference provides a new experimental model to study mechanisms and consequences of LINE-1 activation in the etiology and progression of UC as well as presumably other cancers.

DOI: https://doi.org/10.1038/s41598-020-60796-8
Front Plant Sci. 2020 ;11 46

Proline Biosynthesis Enzyme Genes Confer Salt Tolerance to Switchgrass (Panicum virgatum L.) in Cooperation With Polyamines Metabolism.

Cong Guan, Xin Cui, Hua-Yue Liu, Xue Li, Meng-Qi Li, Yun-Wei Zhang.

  Understanding the regulation of proline metabolism necessitates the suppression of two Δ1-pyrroline-5-carboxylate synthetase enzyme (P5CS) genes performed in switchgrass (Panicum virgatum L.). The results reveal that overexpressing PvP5CS1 and PvP5CS2 increased salt tolerance. Additionally, transcript levels of spermidine (Spd) and spermine (Spm) synthesis and metabolism related genes were upregulated in PvP5CS OE-transgenic plants and downregulated in the PvP5CS RNAi transformants. According to salt stress assay and the measurement of transcript levels of Polyamines (PAs) metabolism-related genes, P5CS enzyme may not only be the key regulator of proline biosynthesis in switchgrass, but it may also indirectly affect the entire subset of pathway for ornithine to proline or to putrescine (Put). Furthermore, application of proline prompted expression levels of Spd and Spm synthesis and metabolism-related genes in both PvP5CS-RNAi and WT plants, but transcript levels were even lower in PvP5CS-RNAi compared to WT plants under salt stress condition. These results suggested that exogenous proline could accelerate polyamines metabolisms under salt stress. Nevertheless, the enzymes involved in this process and the potential functions remain poorly understood. Thus, the aim of this study is to reveal how proline functions with PAs metabolism under salt stress in switchgrass.

Keywords:  PvP5CS1 and PvP5CS2; polyamines; proline; salt stress; switchgrass

DOI:  https://doi.org/10.3389/fpls.2020.00046
Foods. 2020 Mar 02. pii: E267. [Epub ahead of print]9(3):

Exogenous Spermidine Promotes γ-Aminobutyric Acid Accumulation and Alleviates the Negative Effect of NaCl Stress in Germinating Soybean (Glycine max L.).

Weiming Fang, Fei Qi, Yongqi Yin, Zhengfei Yang.

  We investigated the effects of exogenous spermidine (Spd) on the physiological status, γ-aminobutyric acid (GABA) synthase activity, and gene expressions in germinating soybeans under NaCl stress. The results show that Spd significantly increases sprout growth and biomass, decreases malonaldehyde and H2O2 contents, and markedly promotes the activities of superoxide dismutase, catalase, peroxidase, and glutathione peroxidase of germinating soybeans. The harmful effect of NaCl stress was alleviated by exogenous Spd. GABA accumulation in germinating soybeans was caused by the activation of diamine oxidase, polyamine oxidase, aminoaldehyde dehydrogenase, and glutamate decarboxylase activities and by up-regulating their gene expression under Spd-NaCl treatment. The GABA content decreased by 57% and 46% in germinating soybeans with the application of aminoguanidine under Spd and Spd-NaCl treatments, respectively. In conclusion, spermidine induces the accumulation of GABA and increases sprouts biomass, thereby enhancing the functional quality of germinating soybeans.

Keywords:  NaCl stress; germinating soybeans; spermidine; γ-aminobutyric acid

DOI:  https://doi.org/10.3390/foods9030267