| Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas. | |
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MedLine Citation:
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PMID: 19503098 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The chimera nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the tyrosine kinase activity of which is constitutively upregulated, is the causative agent of 75% of the anaplastic large-cell lymphomas (ALCLs). We have demonstrated that NPM-ALK induces the production of reactive oxygen species (ROS) by a pathway involving the arachidonic acid-metabolizing enzymes of the lipoxygenase (LOX) family. The use of the LOX inhibitor nordihydroguaiaretic acid (NDGA) and of the anti-oxidant N-acetylcysteine (NAC) demonstrated that ROS are important in maintaining the ALK kinase active. Consistent with this, NDGA treatment resulted in the inhibition of key pathways, such as Akt, signal transducer and activator of transcription factor 3 (STAT3) and extracellular signal-regulated kinase (ERK), which are involved in NPM-ALK antiapoptotic and pro-mitogenic functions. Conversely, the stress-activated kinase p38, described in some instances as a mediator of apoptosis, was activated. Interestingly, 5-LOX, an isoform involved in many cancers, was found to be activated in NPM-ALK(+) cells. Functional studies have shown that transforming properties, namely proliferation and resistance to apoptosis, were abrogated by treatment with either NDGA or the 5-LOX inhibitor (N-(3-phenoxycinnamyl)-acetohydroxamic acid) (BW A4C). Together, these data point to the ROS/LOX pathway as a potential new target for therapy in NPM-ALK-positive tumors. |
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Authors:
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K Thornber; A Colomba; L Ceccato; G Delsol; B Payrastre; F Gaits-Iacovoni |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-06-08 |
Journal Detail:
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Title: Oncogene Volume: 28 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-07-23 Completed Date: 2009-08-10 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 2690-6 Citation Subset: IM |
Affiliation:
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INSERM, U563, Département Oncogénèse, Signalisation et Innovation Thérapeutique, Toulouse, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis Arachidonate 5-Lipoxygenase / antagonists & inhibitors, metabolism* Cell Line, Tumor Humans Lipoxygenase Inhibitors / pharmacology Lymphoma, Large-Cell, Anaplastic / enzymology, pathology* Nordihydroguaiaretic Acid / analysis Protein-Tyrosine Kinases / metabolism* Reactive Oxygen Species / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Lipoxygenase Inhibitors; 0/Reactive Oxygen Species; 500-38-9/Nordihydroguaiaretic Acid; EC 1.13.11.34/Arachidonate 5-Lipoxygenase; EC 2.7.1.-/p80(NPM-ALK) protein; EC 2.7.10.1/Protein-Tyrosine Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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