Abstract
We provide evidence that arsenic trioxide (As(2)O(3)) targets the BCR-ABL oncoprotein via a novel mechanism involving p62/SQSTM1-mediated localization of the oncoprotein to the autolysosomes and subsequent degradation mediated by the protease cathepsin B. Our studies demonstrate that inhibitors of autophagy or cathepsin B activity and/or molecular targeting of p62/SQSTM1, Atg7, or cathepsin B result in partial reversal of the suppressive effects of AS(2)O(3) on BCR-ABL expressing leukemic progenitors, including primitive leukemic precursors from chronic myelogenous leukemia (CML) patients. Altogether, these findings indicate that autophagic degradation of BCR-ABL is critical for the induction of the antileukemic effects of As(2)O(3) and raise the potential for future therapeutic approaches to target BCR-ABL expressing cells by modulating elements of the autophagic machinery to promote BCR-ABL degradation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Antineoplastic Agents / pharmacology*
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Arsenic Trioxide
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Arsenicals / pharmacology*
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Autophagy / drug effects*
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Autophagy / genetics
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Autophagy-Related Protein 7
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Cathepsin B / antagonists & inhibitors
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Cathepsin B / genetics
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Cathepsin B / metabolism
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Enzyme Inhibitors / pharmacology
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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K562 Cells
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Lysosomes / drug effects
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Lysosomes / metabolism
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Oxides / pharmacology*
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Phosphorylation
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Plasmids
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Primary Cell Culture
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Proteolysis / drug effects
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Sequestosome-1 Protein
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Transfection
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Ubiquitin-Activating Enzymes / antagonists & inhibitors
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Ubiquitin-Activating Enzymes / genetics
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Ubiquitin-Activating Enzymes / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Arsenicals
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Enzyme Inhibitors
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Oxides
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SQSTM1 protein, human
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Sequestosome-1 Protein
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Fusion Proteins, bcr-abl
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CTSB protein, human
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Cathepsin B
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ATG7 protein, human
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Autophagy-Related Protein 7
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Ubiquitin-Activating Enzymes
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Arsenic Trioxide