Chronic myelogenous leukemia (CML) inevitably progresses to a blast phase by mechanisms that are not well understood. The MUC1-C oncoprotein is expressed in CML blasts but not chronic phase cells. The present studies demonstrate that treatment of KU812 and K562 CML cells with a cell-penetrating MUC1-C inhibitor, designated GO-203, is associated with increases in reactive oxygen species (ROS) and depletion of glutathione. GO-203 treatment resulted in the complete downregulation of Bcr-Abl expression and induced cell cycle arrest by a ROS-mediated mechanism that was blocked by the antioxidant N-acetylcysteine. Progression of CML to blast crisis has been linked to dysregulation of Wnt/β-catenin signaling and an arrest of differentiation. The present results show that inhibition of MUC1-C induces ROS-mediated suppression of β-catenin expression and induction of a differentiated myeloid phenotype. Our studies also show that GO-203 treatment is associated with ROS-induced decreases in ATP and loss of survival by late apoptosis/necrosis. These findings demonstrate that inhibition of the MUC1-C oncoprotein in CML cells disrupts redox balance and thereby 1) downregulates expression of both Bcr-Abl and β-catenin and 2) induces terminal myeloid differentiation by ROS-mediated mechanisms.
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