Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide.
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.
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
Dennis J
DJ
Goussetis
Elias
E
Gounaris
Edward J
EJ
Wu
Eliza
E
Vakana
Bhumika
B
Sharma
Matthew
M
Bogyo
Jessica K
JK
Altman
Leonidas C
LC
Platanias
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071193:Autophagy-Related Protein 7; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation; D010957:Plasmids; D061251:Primary Cell Culture; D059748:Proteolysis / Q000187:drug effects; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014162:Transfection; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001152:Arsenicals; D004791:Enzyme Inhibitors; D010087:Oxides; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D016044:Fusion Proteins, bcr-abl; C533912:CTSB protein, human; D002401:Cathepsin B; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D000077237:Arsenic Trioxide