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Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis

Nencioni, Alessio
Hua, Fei
Dillon, Christopher P
Yokoo, Rayka
Cardone, Mike H
Barbieri, Eleonora
Rocco, Ilaria
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Published in Blood. 2005, vol. 105, no. 8, p. 3255-62
Abstract Proteasome inhibitors exhibit antitumor activity against malignancies of different histology. Yet, the mechanisms underlying this effect are poorly understood. Recent evidence indicates that antiapoptotic factors may also accumulate as a consequence of exposure to these drugs, possibly reducing their cytotoxicity. These include the Bcl-2 family member Mcl-1, whose down-regulation has been proposed to initiate apoptosis in response to genotoxic stimuli. In this study, we found that proteasome inhibitors release cyotochrome c and second mitochondria-derived activator of caspase (SMAC)/Diablo and trigger the subsequent apoptotic cascade in spite of concomitant Mcl-1 increase. However, our data indicate that subtraction of Mcl-1 during apoptosis, although not required for early release of proapoptotic factors, is probably relevant in speeding up cell demise, since RNA interference-mediated Mcl-1 silencing is lethal in lymphoma cells. Consistent with this, the cytotoxic effects of proteasome inhibitors are enhanced when Mcl-1 increase is impeded. Thus, this study identifies Mcl-1 accumulation as an unwanted molecular consequence of exposure to proteasome inhibitors, which slows down their proapoptotic effects. Pharmacologic or genetic approaches targeting Mcl-1, including therapeutic RNAi, may increase the effectiveness of these compounds.
Keywords Acetylcysteine/analogs & derivatives/pharmacologyApoptosis/drug effects/physiologyCarrier Proteins/metabolismCaspases/metabolismCell Survival/immunologyComplement Membrane Attack ComplexComplement System ProteinsCysteine Proteinase Inhibitors/pharmacologyCytochromes c/metabolismGene Expression/immunologyGlycoproteins/metabolismHumansIntracellular Signaling Peptides and ProteinsJurkat CellsLeupeptins/pharmacologyLymphocytes/cytology/drug effects/physiologyMitochondria/metabolismMitochondrial Proteins/metabolismMyeloid Cell Leukemia Sequence 1 ProteinNeoplasm Proteins/genetics/metabolismOligopeptides/pharmacologyProteasome Endopeptidase Complex/metabolismProteasome InhibitorsProto-Oncogene Proteins c-bcl-2/genetics/metabolismRNA Interference
PMID: 15613543
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Research group Groupe Christoph Scheiermann (995)
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NENCIONI, Alessio et al. Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis. In: Blood, 2005, vol. 105, n° 8, p. 3255-62. doi: 10.1182/blood-2004-10-3984

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Deposited on : 2018-11-28

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