Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 681-689 |
| Number of pages | 9 |
| Journal | European Journal of Immunology |
| Volume | 36 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2006 |
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Keywords
- Apoptosis
- Cancer
- Dendritic cells
- Proteasome
ASJC Scopus subject areas
- Immunology
Cite this
Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cells. / Nencioni, Alessio; Garuti, Anna; Schwarzenberg, Karin; Cirmena, Gabriella; Dal Bello, Giovanna; Rocco, Ilaria; Barbieri, Eleonora; Brossart, Peter; Patrone, Franco; Ballestrero, Alberto.
In: European Journal of Immunology, Vol. 36, No. 3, 03.2006, p. 681-689.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cells
AU - Nencioni, Alessio
AU - Garuti, Anna
AU - Schwarzenberg, Karin
AU - Cirmena, Gabriella
AU - Dal Bello, Giovanna
AU - Rocco, Ilaria
AU - Barbieri, Eleonora
AU - Brossart, Peter
AU - Patrone, Franco
AU - Ballestrero, Alberto
PY - 2006/3
Y1 - 2006/3
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Cancer
KW - Dendritic cells
KW - Proteasome
UR - http://www.scopus.com/inward/record.url?scp=33644958956&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644958956&partnerID=8YFLogxK
U2 - 10.1002/eji.200535298
DO - 10.1002/eji.200535298
M3 - Article
C2 - 16479541
AN - SCOPUS:33644958956
VL - 36
SP - 681
EP - 689
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 3
ER -