ArticleCancer research2008
Ornithine decarboxylase inhibition by alpha-difluoromethylornithine activates opposing signaling pathways via phosphorylation of both Akt/protein kinase B and p27Kip1 in neuroblastoma.
Article in Cancer research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 67 citations in OpenAlex.
- A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.International journal of cancer · 2020Trial
- Maintenance DFMO Increases Survival in High Risk Neuroblastoma.Scientific reports · 2018Trial
- β-Thujaplicin modulates the ODC-ROS-linked apoptosis in H460 lung cancer cells.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Refractory Hyperammonemic Encephalopathy as a Paraneoplastic Presentation of Fibrolamellar Hepatocellular Carcinoma: A Case Report.The American journal of case reports · 2026Article
- Article
- Targeted therapies in pediatric oncology: A start.Molecular therapy. Oncology · 2026Review
- Design, Synthesis, and Biological Activity of Novel Ornithine Decarboxylase (ODC) Inhibitors.Journal of medicinal chemistry · 2025Article
- Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia.Molecular psychiatry · 2024Article
- Bachmann-Bupp syndrome and treatment.Developmental medicine and child neurology · 2024Review
- Eggs of the mosquito Aedes aegypti survive desiccation by rewiring their polyamine and lipid metabolism.PLoS biology · 2023Article
- Deregulation of the cyclin-dependent kinase inhibitor p27 as a putative candidate for transformation inAIMS microbiology · 2023Article
- Identification of Let-7 miRNA Activity as a Prognostic Biomarker of SHH Medulloblastoma.Cancers · 2021Article
- Article
- Allicin, a Potent New Ornithine Decarboxylase Inhibitor in Neuroblastoma Cells.Journal of natural products · 2020Article
- Purification and Characterization of Ornithine Decarboxylase fromMolecules (Basel, Switzerland) · 2019Article
- Polyamine Metabolism as a Therapeutic Target inHedgehog-Driven Basal Cell Carcinomaand Medulloblastoma.Cells · 2019Review
- Polyamine synthesis as a target ofThe Journal of biological chemistry · 2018Review
- Novel Therapies for Relapsed and Refractory Neuroblastoma.Children (Basel, Switzerland) · 2018Review
- Polyamine Biosynthetic Pathway as a Drug Target for Osteosarcoma Therapy.Medical sciences (Basel, Switzerland) · 2018Article
- Evaluation of Polyamine Transport Inhibitors in a Drosophila Epithelial Model Suggests the Existence of Multiple Transport Systems.Medical sciences (Basel, Switzerland) · 2017Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Ornithine decarboxylase (ODC) is a key enzyme in mammalian polyamine biosynthesis that is up-regulated in various types of cancer. We previously showed that treating human neuroblastoma (NB) cells with the ODC inhibitor alpha-difluoromethylornithine (DFMO) depleted polyamine pools and induced G1 cell cycle arrest without causing apoptosis. However, the precise mechanism by which DFMO provokes these changes in NB cells remained unknown. Therefore, we further examined the effects of DFMO, alone and in combination with phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or Akt/protein kinase B (PKB) inhibitor IV, on the regulation of cell survival and cell cycle-associated pathways in LAN-1 NB cells. In the present study, we found that the inhibition of ODC by DFMO promotes cell survival by inducing the phosphorylation of Akt/PKB at residue Ser473 and glycogen synthase kinase-3beta at Ser9. Intriguingly, DFMO also induced the phosphorylation of p27Kip1 at residues Ser10 (nuclear export) and Thr198 (protein stabilization) but not Thr187 (proteasomal degradation). The combined results from this study provide evidence for a direct cross-talk between ODC-dependent metabolic processes and well-established cell signaling pathways that are activated during NB tumorigenesis. The data suggest that inhibition of ODC by DFMO induces two opposing pathways in NB: one promoting cell survival by activating Akt/PKB via the PI3K/Akt pathway and one inducing p27Kip1/retinoblastoma-coupled G1 cell cycle arrest via a mechanism that regulates the phosphorylation and stabilization of p27Kip1. This study presents new information that may explain the moderate efficacy of DFMO monotherapy in clinical trials and reveals potential new targets for DFMO-based combination therapies for NB treatment.
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