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

Laussmann, M A, Passante, Egle, Düssmann, H, Rauen, J A, Würstle, M L, Delgado, M E, Devocelle, M, Prehn, J H M and Rehm, M (2011) Proteasome inhibition can induce an autophagy-dependent apical activation of caspase-8. Cell Death and Differentiation, 18 (10). pp. 1584-1597. ISSN 1350-9047

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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)aminopropanoylamino) butylboronic acid), epoxomicin (N-acetyl-N-methyl-lisoleucyl-L-isoleucyl-N-(1S)- 3-methyl-1-(2R)-2-methyloxiranylcarbonylbutyl-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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