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

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9437445 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5403 (Electronic) Linking ISSN: 13509047 NLM ISO Abbreviation: Cell Death Differ Subsets: MEDLINE

Publication: <2003->: London : Nature Publishing Group
Original Publication: London : Edward Arnold, c1994-

Autophagy/*physiology ; Caspase 8/*metabolism ; Proteasome Endopeptidase Complex/*metabolism ; Proto-Oncogene Proteins c-bcl-2/*metabolism; Animals ; Apoptosis/genetics ; Apoptosis/physiology ; Autophagy/genetics ; Autophagy-Related Protein 5 ; Boronic Acids/pharmacology ; Bortezomib ; Caspase 3/metabolism ; Caspase 7/metabolism ; Caspase 8/genetics ; Fas-Associated Death Domain Protein/metabolism ; Flow Cytometry ; Fluorescence Resonance Energy Transfer ; HeLa Cells ; Humans ; Immunoblotting ; Mice ; Mice, Mutant Strains ; Microscopy, Fluorescence ; Microtubule-Associated Proteins ; Peptide Hydrolases/metabolism ; Proteasome Endopeptidase Complex/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics ; Pyrazines/pharmacology ; X-Linked Inhibitor of Apoptosis Protein/antagonists & inhibitors ; X-Linked Inhibitor of Apoptosis Protein/genetics ; X-Linked Inhibitor of Apoptosis Protein/metabolism

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 ([(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid), epoxomicin (N-acetyl-N-methyl-lisoleucyl-L-isoleucyl-N-[(1S)-3-methyl-1-[[(2R)-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.

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09/RFP/BIC2375 Ireland SFI_ Science Foundation Ireland; RP/2006/258 Ireland HRBI_ Health Research Board; RP/2008/7 Ireland HRBI_ Health Research Board

Indexing Agency: NLM Local ID #: UKMS34496.

0 (ATG5 protein, human)
0 (Autophagy-Related Protein 5)
0 (Boronic Acids)
0 (FADD protein, human)
0 (Fas-Associated Death Domain Protein)
0 (Microtubule-Associated Proteins)
0 (Proto-Oncogene Proteins c-bcl-2)
0 (Pyrazines)
0 (X-Linked Inhibitor of Apoptosis Protein)
0 (XIAP protein, human)
69G8BD63PP (Bortezomib)
EC 3.4.- (Peptide Hydrolases)
EC 3.4.22.- (Caspase 3)
EC 3.4.22.- (Caspase 7)
EC 3.4.22.- (Caspase 8)
EC 3.4.25.1 (Proteasome Endopeptidase Complex)
EC 3.4.99.- (DEVDase)

Date Created: 20110402 Date Completed: 20120420 Latest Revision: 20220316

20221213

PMC3130899

10.1038/cdd.2011.27

21455219