bims-polyam Biomed News
on Polyamines
Issue of 2022–12–04
six papers selected by
Sebastian J. Hofer, University of Graz
  1. DMSO-tolerant ornithine decarboxylase (ODC) tandem assay optimised for high-throughput screening.
  2. MicroRNA-378a-3p prevents initiation and growth of colorectal cancer by fine tuning polyamine synthesis.
  3. Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment.
  4. Alterations in the omics profiles in mevalonate pathway-inhibited cancer cells.
  5. Cardiac PI3K p110α attenuation delays aging and extends lifespan.
  6. ATP13A2 modifies mitochondrial localization of overexpressed TOM20 to autolysosomal pathway.
  1. J Enzyme Inhib Med Chem. 2023 Dec;38(1): 309-318
    DMSO-tolerant ornithine decarboxylase (ODC) tandem assay optimised for high-throughput screening.
    Mingu Gordon Park, Suyeon Yellena Kim, C Justin Lee.
      Ornithine decarboxylase (ODC), the first rate-limiting enzyme in polyamine synthesis, has emerged as a therapeutic target for cancer and Alzheimer's disease (AD). To inhibit ODC, α-difluoromethylornithine (DFMO), an irreversible ODC inhibitor, has been widely used. However, due to its poor pharmacokinetics, the need for discovery of better ODC inhibitors is inevitable. For high-throughput screening (HTS) of ODC inhibitors, an ODC enzyme assay using supramolecular tandem assay has been introduced. Nevertheless, there has been no study utilising the ODC tandem assay for HTS, possibly due to its intolerability to dimethyl sulfoxide (DMSO), a common amphipathic solvent used for drug libraries. Here we report a DMSO-tolerant ODC tandem assay in which DMSO-dependent fluorescence quenching becomes negligible by separating enzyme reaction and putrescine detection. Furthermore, we optimised human cell-line-based mass production of ODC for HTS. Our newly developed assay can be a crucial first step in discovering more effective ODC modulators than DFMO.
    Keywords:  Dimethyl sulfoxide; Ornithine decarboxylase; cucurbit[6]uril; high-throughput screening assay; trans-4-(4-(dimethylamino)-styryl)-1-methylpyridinium iodide
    DOI:  https://doi.org/10.1080/14756366.2022.2150186
  2. Cell Biosci. 2022 Dec 01. 12(1): 192
    MicroRNA-378a-3p prevents initiation and growth of colorectal cancer by fine tuning polyamine synthesis.
    Ningning Liu, Tianpeng Zhang, Clifford J Steer, Guisheng Song.
       BACKGROUND: Inhibitors of ornithine decarboxylase (ODC) are effective at preventing colorectal cancer (CRC). However, their high toxicity limits their clinical application. This study was aimed to explore the potential of microRNAs (miRNAs) as an inhibitor of ODC.
    METHODS: miRNA array was used to identify dysregulated miRNAs in CRC tumors of mice and patients. Azoxymethane (AOM)/Dextran Sodium Sulfate (DSS) were used to induce CRC in mice. miRNA function in carcinogenesis was determined by soft-agar colony formation, flow cytometry, and wound healing of CRC cells. Mini-circle was used to deliver miRNA into colons.
    RESULTS: MiRNA profiling identified miR-378a-3p (miR-378a) as the most reduced miRNA in CRC tumors of patients and mice treated with AOM/DSS. Pathway array analysis revealed that miR-378a impaired c-MYC and ODC1 pathways. Further studies identified FOXQ1 (forkhead box Q1) and ODC1 as two direct targets of miR-378a. FOXQ1 activated transcription of c-MYC, a transcription activator of ODC1. In addition to directly targeting ODC1, miR-378a also inhibited expression of ODC1 via the FOXQ1-cMYC axis, thereby inhibiting polyamine synthesis in human CRC cells. Phenotypically, by reducing polyamine synthesis, miR-378a induced apoptosis and inhibited proliferation and migration of CRC cells, while disrupting the association of miR-378a with FOXQ1 and ODC1 offset the effects of miR-378a, suggesting that FOXQ1 and ODC1 were required for miR-378a to inhibit CRC cell growth. MiR-378a treatment robustly prevented growth of HCC by inhibiting polyamine synthesis in AOM/DSS mice.
    CONCLUSION: MiR-378a prevents CRC by inhibiting polyamine synthesis, suggesting its use as a novel ODC inhibitor against CRC.
    Keywords:  Non-coding RNA; Ornithine decarboxylase inhibitor; c-Myc signaling
    DOI:  https://doi.org/10.1186/s13578-022-00930-3
  3. Pediatr Dermatol. 2022 Nov 28.
    Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment.
    Antara Afrin, Tonia S Afshan, Elizabeth A VanSickle, Julianne Michael, Rachel L Laarman, Caleb P Bupp.
      Bachmann-Bupp syndrome (OMIM #619075) is a novel autosomal dominant disorder caused by variants in the c-terminus of the ornithine decarboxylase 1 gene, resulting in increased levels of ornithine decarboxylase. This case report includes two patients diagnosed with Bachmann-Bupp syndrome who were treated with difluoromethylornithine through compassionate use approval from the United States Food and Drug Administration. In both patients, treatment with difluoromethylornithine has resulted in improved dermatologic signs, including regrowth of eyebrow and scalp hair and cessation of recurrent follicular cyst development.
    Keywords:  alopecia; difluoromethylornithine; drug therapy; follicular cyst; ornithine decarboxylase
    DOI:  https://doi.org/10.1111/pde.15187
  4. Life Sci. 2022 Nov 28. pii: S0024-3205(22)00949-3. [Epub ahead of print] 121249
    Alterations in the omics profiles in mevalonate pathway-inhibited cancer cells.
    Tomoko Warita, Nanami Irie, Yaxuan Zhou, Jiro Tashiro, Akihiro Sugiura, Zoltán N Oltvai, Katsuhiko Warita.
       AIMS: Statins, cholesterol-lowering drugs, are potential therapeutic agents for inhibiting cancer proliferation. However, the mechanisms that mediate the effects of statins, the homeostatic responses of tumor cells to statin therapy, and the modes underlying the antitumor effects of statins remain unclear.
    MAIN METHODS: To uncover the effects of statins on cancer cells in vitro, we performed transcriptome and metabolome analyses on atorvastatin-treated statin-resistant and statin-sensitive lung cancer cells.
    KEY FINDINGS: The results of Gene Ontology terms and pathway enrichment analyses showed that after 24 h of atorvastatin treatment, the expression of cell cycle- and DNA replication-related genes was significantly decreased in the statin-sensitive cancer cells. The results of metabolome analysis showed that the components of polyamine metabolism and purine metabolism, glycolysis, and pentose phosphate pathway were decreased in the statin-sensitive cancer cells.
    SIGNIFICANCE: Differences in cellular properties between statin-sensitive and statin-resistant cancer cells revealed additional candidates for therapeutic targets in statin-treated cancer cells and suggested that inhibiting these metabolic pathways could improve efficacy. In conclusion, combining statins with inhibitors of polyamine metabolism (cell proliferation and protein translation), purine metabolism (DNA synthesis), glycolytic system (energy production), and pentose phosphate pathway (antioxidant stress) might enhance the anticancer effects of statins.
    Keywords:  Cancer cells; Glycolysis; Metabolome; Polyamine metabolism; Statins; Transcriptome
    DOI:  https://doi.org/10.1016/j.lfs.2022.121249
  5. Cell Stress. 2022 Aug;6(8): 72-75
    Cardiac PI3K p110α attenuation delays aging and extends lifespan.
    Mahmoud Abdellatif, Tobias Eisenberg, Alexander Martin Heberle, Kathrin Thedieck, Guido Kroemer, Simon Sedej.
      Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular me-tabolism and growth. Loss-of-function mutations in PI3K signaling and other downstream effectors of the insulin signaling pathway extend the lifespan of various model organisms. However, the pro-longevity effect appears to be sex-specific and young mice with reduced PI3K signaling have increased risk of cardiac disease. Hence, it remains elusive as to whether PI3K inhibition is a valid strategy to delay aging and extend healthspan in humans. We recently demonstrated that reduced PI3K activity in cardiomyocytes delays cardiac growth, causing subnormal contractility and cardiopulmonary functional capacity, as well as increased risk of mortality at young age. In stark contrast, in aged mice, experi-mental attenuation of PI3K signaling reduced the age-dependent decline in cardiac function and extended maximal lifespan, suggesting a biphasic effect of PI3K on cardiac health and survival. The cardiac anti-aging effects of reduced PI3K activity coincided with enhanced oxida-tive phosphorylation and required increased autophagic flux. In humans, explanted failing hearts showed in-creased PI3K signaling, as indicated by increased phos-phorylation of the serine/threonine-protein kinase AKT. Hence, late-life cardiac-specific targeting of PI3K might have a therapeutic potential in cardiac aging and related diseases.
    Keywords:  IGF1; PI3K; aging; autophagy; cardiomyopathy; heart failure; insulin signaling; mitochondrial dysfunction
    DOI:  https://doi.org/10.15698/cst2022.08.270
  6. PLoS One. 2022 ;17(11): e0276823
    ATP13A2 modifies mitochondrial localization of overexpressed TOM20 to autolysosomal pathway.
    Yuta Hatori, Yukina Kanda, Saori Nonaka, Hiroshi Nakanishi, Takeo Kitazawa.
      Mutations in ATP13A2 cause Kufor-Rakeb Syndrome (KRS), a juvenile form of Parkinson's Disease (PD). The gene product belongs to a diverse family of ion pumps and mediates polyamine influx from lysosomal lumen. While the biochemical and structural studies highlight its unique mechanics, how PD pathology is linked to ATP13A2 function remains unclear. Here we report that localization of overexpressed TOM20, a mitochondrial outer-membrane protein, is significantly altered upon ATP13A2 expression to partially merge with lysosome. Using Halo-fused version of ATP13A2, ATP13A2 was identified in lysosome and autophagosome. Upon ATP13A2 co-expression, overexpressed TOM20 was found not only in mitochondria but also within ATP13A2-containing autolysosome. This modification of TOM20 localization was inhibited by adding 1-methyl-4-phenylpyridinium (MPP+) and not accompanied with mitophagy induction. We suggest that ATP13A2 may participate in the control of overexpressed proteins targeted to mitochondrial outer-membrane.
    DOI:  https://doi.org/10.1371/journal.pone.0276823
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