Abstract
Resistance to Imatinib mesylate (IM) is an emerging problem for patients with chronic myelogenous leukemia (CML). T315I mutation in the Bcr-Abl is the predominant mechanism of the acquired resistance to IM and second generation tyrosine kinase inhibitors (TKI). Therefore it is urgent to search for new measures to overcome TKI-resistance. Auranofin (AF), clinically used to treat rheumatic arthritis, was recently approved by US Food and Drug Administration for Phase II clinical trial to treat cancer. In contrast to the reports that AF induces apoptosis by increasing intracellular reactive oxygen species (ROS) levels via inhibiting thioredoxin reductase, our recent study revealed that AF-induced apoptosis depends on inhibition of proteasomal deubiquitinases (UCHL5 and USP14). Here we report that (i) AF induces apoptosis in both Bcr-Abl wild-type cells and Bcr-Abl-T315I mutation cells and inhibits the growth of IM-resistant Bcr-Abl-T315I xenografts in vivo; (ii) AF inhibits Bcr-Abl through both downregulation of Bcr-Abl gene expression and Bcr-Abl cleavage mediated by proteasome inhibition-induced caspase activation; (iii) proteasome inhibition but not ROS is required for AF-induced caspase activation and apoptosis. These findings support that AF overcomes IM resistance through both Bcr/Abl-dependent and -independent mechanisms, providing great clinical significance for cancer treatment.
Highlights
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by a reciprocal translocation between chromosomes 9 and 22, resulting in the expression of a fusion oncoprotein, Bcr-Abl, which is found in nearly 95% CML patients [1]
KBM5 (Bcr-Abl wild-type) cells are sensitive to Imatinib mesylate (IM) while KBM5-T315I (Bcr-Abl-T315I) cells are very resistant to IM [13, 28]
To investigate the effect of AF on the growth of CML cells, KBM5 and KBM5-T315I cells were treated with AF in vitro for 48 hours and cell viability was detected by the MTS assay
Summary
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by a reciprocal translocation between chromosomes 9 and 22, resulting in the expression of a fusion oncoprotein, Bcr-Abl, which is found in nearly 95% CML patients [1]. The aberrant tyrosine kinase activity of this chimeric protein www.impactjournals.com/oncotarget is responsible for malignant transformation by activating multiple signal transduction pathways, including the MAPK/ERK cascade, PI3K/Akt, and STATs [2,3,4]. Activation of these pathways in Bcr-Abl expressing cells results in increased expression of several antiapoptotic proteins, such as Bcl-2, Bcl-xL, Mcl-1, XIAP, leading to advantaged cell survival [5,6,7]. Novel strategies to overcome IM resistance are desperately needed To this end, ponatinib has been established as a third generation TKI, which suggests that inhibiting Bcr-Abl expression is a promising approach [17]
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