en
Scientific article
English

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

Published inBlood, vol. 105, no. 8, p. 3255-3262
Publication date2005
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/pharmacology
  • Apoptosis/drug effects/physiology
  • Carrier Proteins/metabolism
  • Caspases/metabolism
  • Cell Survival/immunology
  • Complement Membrane Attack Complex
  • Complement System Proteins
  • Cysteine Proteinase Inhibitors/pharmacology
  • Cytochromes c/metabolism
  • Gene Expression/immunology
  • Glycoproteins/metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Jurkat Cells
  • Leupeptins/pharmacology
  • Lymphocytes/cytology/drug effects/physiology
  • Mitochondria/metabolism
  • Mitochondrial Proteins/metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins/genetics/metabolism
  • Oligopeptides/pharmacology
  • Proteasome Endopeptidase Complex/metabolism
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
  • RNA Interference
Affiliation Not a UNIGE publication
Citation (ISO format)
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. 3255–3262. doi: 10.1182/blood-2004-10-3984
Main files (1)
Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal0006-4971
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