Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein.

Hdl Handle:
http://hdl.handle.net/10147/322353
Title:
Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein.
Authors:
Elzinga, Baukje M; Nyhan, Michelle J; Crowley, Lisa C; O'Donovan, Tracey R; Cahill, Mary R; McKenna, Sharon L
Affiliation:
Leslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute, University College Cork, Cork, Ireland.
Citation:
Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein. 2013, 88 (6):455-62 Am. J. Hematol.
Journal:
American journal of hematology
Issue Date:
Jun-2013
URI:
http://hdl.handle.net/10147/322353
DOI:
10.1002/ajh.23428
PubMed ID:
23440701
Additional Links:
http://onlinelibrary.wiley.com/doi/10.1002/ajh.23428/abstract
Abstract:
Chronic Myeloid Leukemia (CML) is a disease of hematopoietic stem cells which harbor the chimeric gene Bcr-Abl. Expression levels of this constitutively active tyrosine kinase are critical for response to tyrosine kinase inhibitor treatment and also disease progression, yet the regulation of protein stability is poorly understood. We have previously demonstrated that imatinib can induce autophagy in Bcr-Abl expressing cells. Autophagy has been associated with the clearance of large macromolecular signaling complexes and abnormal proteins, however, the contribution of autophagy to the turnover of Bcr-Abl protein in imatinib treated cells is unknown. In this study, we show that following imatinib treatment, Bcr-Abl is sequestered into vesicular structures that co-localize with the autophagy marker LC3 or GABARAP. This association is inhibited by siRNA mediated knockdown of autophagy regulators (Beclin 1/ATG7). Pharmacological inhibition of autophagy also reduced Bcr-Abl/LC3 co-localization in both K562 and CML patient cells. Bcr-Abl protein expression was reduced with imatinib treatment. Inhibition of both autophagy and proteasome activity in imatinib treated cells was required to restore Bcr-Abl protein levels to those of untreated cells. This ability to down-regulate Bcr-Abl protein levels through the induction of autophagy may be an additional and important feature of the activity of imatinib.
Item Type:
Article
Language:
en
MeSH:
Adenine; Animals; Apoptosis Regulatory Proteins; Autophagy; Benzamides; Cell Line, Tumor; Down-Regulation; Fusion Proteins, bcr-abl; Gene Knockdown Techniques; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Membrane Proteins; Mice; Phagosomes; Piperazines; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; Pyrimidines; RNA, Small Interfering; Signal Transduction; Transfection
ISSN:
1096-8652

Full metadata record

DC FieldValue Language
dc.contributor.authorElzinga, Baukje Men_GB
dc.contributor.authorNyhan, Michelle Jen_GB
dc.contributor.authorCrowley, Lisa Cen_GB
dc.contributor.authorO'Donovan, Tracey Ren_GB
dc.contributor.authorCahill, Mary Ren_GB
dc.contributor.authorMcKenna, Sharon Len_GB
dc.date.accessioned2014-07-03T14:10:07Z-
dc.date.available2014-07-03T14:10:07Z-
dc.date.issued2013-06-
dc.identifier.citationInduction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein. 2013, 88 (6):455-62 Am. J. Hematol.en_GB
dc.identifier.issn1096-8652-
dc.identifier.pmid23440701-
dc.identifier.doi10.1002/ajh.23428-
dc.identifier.urihttp://hdl.handle.net/10147/322353-
dc.description.abstractChronic Myeloid Leukemia (CML) is a disease of hematopoietic stem cells which harbor the chimeric gene Bcr-Abl. Expression levels of this constitutively active tyrosine kinase are critical for response to tyrosine kinase inhibitor treatment and also disease progression, yet the regulation of protein stability is poorly understood. We have previously demonstrated that imatinib can induce autophagy in Bcr-Abl expressing cells. Autophagy has been associated with the clearance of large macromolecular signaling complexes and abnormal proteins, however, the contribution of autophagy to the turnover of Bcr-Abl protein in imatinib treated cells is unknown. In this study, we show that following imatinib treatment, Bcr-Abl is sequestered into vesicular structures that co-localize with the autophagy marker LC3 or GABARAP. This association is inhibited by siRNA mediated knockdown of autophagy regulators (Beclin 1/ATG7). Pharmacological inhibition of autophagy also reduced Bcr-Abl/LC3 co-localization in both K562 and CML patient cells. Bcr-Abl protein expression was reduced with imatinib treatment. Inhibition of both autophagy and proteasome activity in imatinib treated cells was required to restore Bcr-Abl protein levels to those of untreated cells. This ability to down-regulate Bcr-Abl protein levels through the induction of autophagy may be an additional and important feature of the activity of imatinib.en_GB
dc.language.isoenen
dc.relation.urlhttp://onlinelibrary.wiley.com/doi/10.1002/ajh.23428/abstracten_GB
dc.rightsArchived with thanks to American journal of hematologyen_GB
dc.subject.meshAdenine-
dc.subject.meshAnimals-
dc.subject.meshApoptosis Regulatory Proteins-
dc.subject.meshAutophagy-
dc.subject.meshBenzamides-
dc.subject.meshCell Line, Tumor-
dc.subject.meshDown-Regulation-
dc.subject.meshFusion Proteins, bcr-abl-
dc.subject.meshGene Knockdown Techniques-
dc.subject.meshHumans-
dc.subject.meshK562 Cells-
dc.subject.meshLeukemia, Myelogenous, Chronic, BCR-ABL Positive-
dc.subject.meshMembrane Proteins-
dc.subject.meshMice-
dc.subject.meshPhagosomes-
dc.subject.meshPiperazines-
dc.subject.meshProteasome Endopeptidase Complex-
dc.subject.meshProtein Kinase Inhibitors-
dc.subject.meshPyrimidines-
dc.subject.meshRNA, Small Interfering-
dc.subject.meshSignal Transduction-
dc.subject.meshTransfection-
dc.titleInduction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein.en_GB
dc.typeArticleen
dc.contributor.departmentLeslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute, University College Cork, Cork, Ireland.en_GB
dc.identifier.journalAmerican journal of hematologyen_GB
dc.description.fundingHEA Higher Education Authorityen
dc.description.provinceMunsteren
dc.description.peer-reviewpeer-reviewen

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