Proteasome inhibition can induce an autophagy-dependent apical activation of caspase-8

Antiapoptotic Bcl-2 family proteins are often highly expressed in chemotherapy-resistant cancers and impair mitochondrial outer membrane permeabilisation (MOMP), an important requirement for caspase activation via the intrinsic apoptosis pathway. Interestingly, although Bcl-2 overexpression in HeLa...

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Bibliographic Details
Published in:	Cell death and differentiation Vol. 18; no. 10; pp. 1584 - 1597
Main Authors:	Laussmann, M A, Passante, E, Düssmann, H, Rauen, J A, Würstle, M L, Delgado, M E, Devocelle, M, Prehn, J H M, Rehm, M
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-10-2011 Nature Publishing Group
Subjects:	631/80/474/2085 631/80/82/39 Animals Apoptosis Apoptosis - genetics Apoptosis - physiology Autophagy Autophagy - genetics Autophagy - physiology Autophagy-Related Protein 5 Biochemistry Biomedical and Life Sciences Boronic Acids - pharmacology Bortezomib Caspase 3 - metabolism Caspase 7 - metabolism Caspase 8 - genetics Caspase 8 - metabolism Cell Biology Cell cycle Cell Cycle Analysis Cell death Fas-Associated Death Domain Protein - metabolism Flow Cytometry Fluorescence Resonance Energy Transfer Health physics HeLa Cells Humans Immunoblotting Life Sciences Ligands Mice Mice, Mutant Strains Microscopy, Fluorescence Microtubule-Associated Proteins Original Paper Peptide Hydrolases - metabolism Physiology Proteasome Endopeptidase Complex - drug effects Proteasome Endopeptidase Complex - metabolism Proteins Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Pyrazines - pharmacology Stem Cells Tumor necrosis factor-TNF X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors X-Linked Inhibitor of Apoptosis Protein - genetics X-Linked Inhibitor of Apoptosis Protein - metabolism Ireland proteasome Förster resonance energy transfer apoptosis caspase-8 autophagy Atg5 Bcl-2 Bortezomib
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Summary:	Antiapoptotic Bcl-2 family proteins are often highly expressed in chemotherapy-resistant cancers and impair mitochondrial outer membrane permeabilisation (MOMP), an important requirement for caspase activation via the intrinsic apoptosis pathway. Interestingly, although Bcl-2 overexpression in HeLa cervical cancer cells abrogated caspase processing in response to intrinsic apoptosis induction by staurosporine, tunicamycin or etoposide, residual caspase processing was observed following proteasome inhibition by bortezomib ([(1 R )-3-methyl-1-({(2 S )-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid), epoxomicin ( N -acetyl- N -methyl-lisoleucyl- L -isoleucyl- N -[(1 S )-3-methyl-1-[[(2 R )-2-methyloxiranyl]carbonyl]butyl]- L -threoninamide) or MG-132 ( N -(benzyloxycarbonyl)leucinylleucinylleucinal). Similar responses were found in Bcl-2-overexpressing H460 NSCLC cells and Bax/Bak-deficient mouse embyronic fibroblasts. Mild caspase processing resulted in low DEVDase activities, which were MOMP independent and persisted for long periods without evoking immediate cell death. Surprisingly, depletion of caspase-3 and experiments in caspase-7-depleted MCF-7-Bcl-2 cells indicated that the DEVDase activity did not originate from effector caspases. Instead, Fas-associated death domain (FADD)-dependent caspase-8 activation was the major contributor to the slow, incomplete substrate cleavage. Caspase-8 activation was independent of death ligands, but required the induction of autophagy and the presence of Atg5. Depletion of XIAP or addition of XIAP-antagonising peptides resulted in a switch towards efficient apoptosis execution, suggesting that the requirement for MOMP was bypassed by activating the caspase-8/caspase-3 axis. Combination treatments of proteasome inhibitors and XIAP antagonists therefore represent a promising strategy to eliminate highly resistant cancer cells, which overexpress antiapoptotic Bcl-2 family members.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1350-9047 1476-5403
DOI:	10.1038/cdd.2011.27