Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cells.
Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen-presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte-derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up-regulation and intracellular redistribution of Bcl-2-associated X protein (Bax), a pro-apoptotic Bcl-2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen-presenting cell level.
Nencioni
Alessio
A
Department of Internal Medicine, University of Genova, Genova, Italy. A.Nencioni@gmx.net
Garuti
Anna
A
Schwarzenberg
Karin
K
Cirmena
Gabriella
G
Dal Bello
Giovanna
G
Rocco
Ilaria
I
Barbieri
Eleonora
E
Brossart
Peter
P
Patrone
Franco
F
Ballestrero
Alberto
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D008928:Mitochondria / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D061988:Proteasome Inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000276:immunology
D000970:Antineoplastic Agents; C494826:BAX protein, human; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D051028:bcl-2-Associated X Protein; D046988:Proteasome Endopeptidase Complex