Abstract
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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Acknowledgements
We thank E Espinos for providing pBSK-NPM–ALK, D Ramel and the group ‘Signaling and Phosphoinosites in normal and pathologic hematopoietic cells’ for helpful discussions. This work was supported by grants from the INSERM, ‘Ministère de la Recherche et de la Technologie’, ARC, INCa, La Ligue contre le Cancer, Cancéropôle GSO and the ‘Pôle de compétitivité Cancer-Biosanté/Fonds uniques interministériels des pôles de compétitivité’.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Thornber, K., Colomba, A., Ceccato, L. et al. Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas. Oncogene 28, 2690–2696 (2009). https://doi.org/10.1038/onc.2009.125
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DOI: https://doi.org/10.1038/onc.2009.125
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