1. ¹INSERM, U563, Département Oncogénèse, Signalisation et Innovation Thérapeutique, Toulouse, France
2. ²Centre de Physiopathologie de Toulouse Purpan, Université Toulouse III Paul-Sabatier, Toulouse, France

Correspondence: Dr F Gaits-Iacovoni, INSERM, U563, Dpt d'Oncogenèse, Signalisation et Innovation Thérapeutique, CHU Purpan, BP 3028, 31024 Toulouse cedex 3, France. E-mail: frederique.gaits@inserm.fr

Received 21 October 2008; Revised 17 April 2009; Accepted 24 April 2009; Published online 8 June 2009.

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.