Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

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.

Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade)

“…Immature monocyte-derived DC appear to be most sensitive to the effects of Bortezomib. [12][13][14] However, the data on the effect of Bortezomib on mature DC are more controversial: although our study shows that mature DC are partially resistant to proteasome inhibition, consistent with a recent study, 13 at least two other studies have shown substantial apoptosis of mature DC upon exposure to Bortezomib. 12,14 The reasons for this discrepancy is unclear, but it may have to do with the different conditions of DC maturation in the different studies.…”

“…[12][13][14] The induction of apoptosis by Bortezomib was a specific feature of cells belonging to the monocyte/DC lineage, as Bortezomib did not reduce recovery (not shown) or induce apoptosis of purified B and T lymphocytes after 24 h of culture, except at doses 450 ng/ml (Figure 2e). Similar results were obtained with purified CD34 þ progenitor cells (Figure 2e).…”

“…9,10 There is extensive evidence that Bortezomib induces the apoptosis of in vitro monocyte-derived immature and mature DCs. [11][12][13][14] However, it is not known whether Bortezomib induces the apoptosis of 'native' DC circulating in the peripheral blood, although it may alter the function of circulating myeloid DC ex vivo. 15 Moreover, the effects of Bortezomib on monocytes have not been thoroughly investigated.…”

Proteasome inhibition attenuates rasfonin-induced autophagy concurring with the upregulation of caspase-dependent apoptosis

“…Former studies indicated that MG132 also involved in apoptosis, playing an either promotion or inhibition role (Grimm et al 1996; Nencioni et al 2006). Therefore, we detected the influence of MG132 on rasfonin-induced apoptosis in the following experiments.…”

“…However, another proteasome inhibitor lactacystin induced apoptosis and the cleavage of PARP-1, while pre-treatment with autophagy enhancer rapamycin attenuated lactacystin-induced apoptosis and reduced lactacystin-induced ubiquitinated protein aggregation in differentiated PC12 cells (Pan et al 2008). Furthermore, MG132 was found to induce apoptosis in human monocyte-derived dendritic cells (Nencioni et al 2006). Here, we clearly demonstrated that MG132-promoted rasfonin induced the cleavage of PARP-1 and functioned synergistically with rasfonin to inhibit cell viability.…”