title: Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis.
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.
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Center for Cancer Research, Cambridge, MA, USA. a.nencioni@gmx.net
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
authors.forename: Fei
authors.initials: F
authors.lastname: Hua
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Dillon
authors.forename: Rayka
authors.initials: R
authors.lastname: Yokoo
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheiermann
authors.forename: Mike H
authors.initials: MH
authors.lastname: Cardone
authors.forename: Eleonora
authors.initials: E
authors.lastname: Barbieri
authors.forename: Ilaria
authors.initials: I
authors.lastname: Rocco
authors.forename: Anna
authors.initials: A
authors.lastname: Garuti
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wesselborg
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.forename: Franco
authors.initials: F
authors.lastname: Patrone
authors.forename: Alberto
authors.initials: A
authors.lastname: Ballestrero
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D007976:Leupeptins / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D015938:Complement Membrane Attack Complex; D015853:Cysteine Proteinase Inhibitors; C412403:DIABLO protein, human; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; D024101:Mitochondrial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C047610:SC5b-9 protein complex; C067713:lactacystin; D003165:Complement System Proteins; D045304:Cytochromes c; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine; C078846:epoxomicin