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Obatoclax induces Atg7-dependent autophagy independent of beclin-1 and BAX/BAK.
- Source :
-
Cell death & disease [Cell Death Dis] 2010 Dec 16; Vol. 1, pp. e108. Date of Electronic Publication: 2010 Dec 16. - Publication Year :
- 2010
-
Abstract
- Direct pharmacological targeting of the anti-apoptotic B-cell lymphoma-2 (BCL-2) family is an attractive therapeutic strategy for treating cancer. Obatoclax is a pan-BCL-2 family inhibitor currently in clinical development. Here we show that, although obatoclax can induce mitochondrial apoptosis dependent on BCL-2 associated x protein/BCL-2 antagonist killer (BAX/BAK) consistent with its on-target pharmacodynamics, simultaneous silencing of both BAX and BAK did not abolish acute toxicity or loss of clonogenicity. This is despite complete inhibition of apoptosis. Obatoclax dramatically reduced viability without inducing loss of plasma membrane integrity. This was associated with rapid processing of light chain-3 (LC3) and reduction of S6 kinase phosphorylation, consistent with autophagy. Dramatic ultrastructural vacuolation, not typical of autophagy, was also induced. Silencing of beclin-1 failed to prevent LC3 processing, whereas knockout of autophagy-related (Atg)7 abolished LC3 processing but failed to prevent obatoclax-induced loss of clonogenicity or ultrastructural changes. siRNA silencing of Atg7 in BAX/BAK knockout mouse embryonic fibroblasts did not prevent obatoclax-induced loss of viability. Cells selected for obatoclax resistance evaded apoptosis independent of changes in BCL-2 family expression and displayed reduced LC3 processing. In summary, obatoclax exhibits BAX- and BAK-dependent and -independent mechanisms of toxicity and activation of autophagy. Mechanisms other than autophagy and apoptosis are blocked in obatoclax resistant cells and contribute significantly to obatoclax's anticancer efficacy.
- Subjects :
- Animals
Apoptosis
Apoptosis Regulatory Proteins physiology
Autophagy-Related Protein 7
Beclin-1
Cell Line, Tumor
Cell Membrane drug effects
Drug Resistance, Neoplasm
Humans
Indoles
Membrane Proteins physiology
Mice
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2 metabolism
Ubiquitin-Activating Enzymes genetics
Ubiquitin-Activating Enzymes metabolism
bcl-2 Homologous Antagonist-Killer Protein genetics
bcl-2 Homologous Antagonist-Killer Protein metabolism
bcl-2-Associated X Protein genetics
bcl-2-Associated X Protein metabolism
Autophagy drug effects
Pyrroles pharmacology
Ubiquitin-Activating Enzymes physiology
bcl-2 Homologous Antagonist-Killer Protein physiology
bcl-2-Associated X Protein physiology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 1
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 21368880
- Full Text :
- https://doi.org/10.1038/cddis.2010.86