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Landry, WD,Woolley, JF,Cotter, TG
2013
January
Leukemia Research
Imatinib and Nilotinib inhibit Bcr-Abl-induced ROS through targeted degradation of the NADPH oxidase subunit p22phox
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Chronic Myelogenous Leukaemia Bcr-Abl Reactive oxygen species NADPH oxidase p22phox Imatinib Nilotinib GSK-3 beta CHRONIC MYELOGENOUS LEUKEMIA SYNTHASE KINASE 3-BETA DOUBLE-STRAND BREAKS ERROR-PRONE REPAIR DNA-DAMAGE GENOMIC INSTABILITY CELLS NOX4 PHOSPHORYLATION PROGRESSION
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Constitutive expression of the Bcr-Abl kinase in Chronic Myelogenous Leukaemia (CML) is known to produce elevated levels of Reactive Oxygen Species (ROS) which can enhance cell survival as well as generate genomic instability. Our laboratory has previously demonstrated that NADPH oxidase (Nox) activity contributes to intracellular-ROS levels in Bcr-Abl-positive cells, while inducing increased pro-survival signalling through the PI3K/Akt pathway. How Bcr-Abl signalling regulates Nox activity still remains to be elucidated. In this study, using the K562 CML cell line we showed that inhibition of Bcr-Abl signalling, by either Imatinib or Nilotinib, led to a significant reduction in ROS levels which was concurrent with the GSK-3 beta dependent, post-translational down-regulation of the small membrane-bound protein p22phox, an essential component of the Nox complex. Furthermore, siRNA knockdown of p22phox in these cells established its importance in ROS production and proliferation. Taken together we believe our results provide a possible link between Bcr-Abl signalling and ROS production through Nox activity and demonstrate a novel mechanism of action associated with Imatinib and Nilotinib treatment in CML. (C) 2012 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.leukres.2012.11.003
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