Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis.
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.
Nencioni
Alessio
A
Massachusetts Institute of Technology, Department of Biology, Center for Cancer Research, Cambridge, MA, USA. a.nencioni@gmx.net
Hua
Fei
F
Dillon
Christopher P
CP
Yokoo
Rayka
R
Scheiermann
Christoph
C
Cardone
Mike H
MH
Barbieri
Eleonora
E
Rocco
Ilaria
I
Garuti
Anna
A
Wesselborg
Sebastian
S
Belka
Claus
C
Brossart
Peter
P
Patrone
Franco
F
Ballestrero
Alberto
A
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
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