Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis

Nencioni, Alessio; Hua, Fei; Dillon, Christopher P.; Yokoo, Rayka; Scheiermann, Christoph; Cardone, Mike H.; Barbieri, Eleonora; Rocco, Ilaria; Garuti, Anna; Wesselborg, Sebastian; Belka, Claus; Brossart, Peter; Patrone, Franco; Ballestrero, Alberto

doi:10.1182/blood-2004-10-3984

Cited by 108 publications

(112 citation statements)

References 36 publications

(57 reference statements)

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“…We as well as other groups have recently confirmed the involvement of the mitochondrial pathway and of caspases in apoptosis due to proteasome inhibition [13][14][15][16][17]. The observation of cytochrome c cytosolic relocalization and DW m dissipation in DC treated with bortezomib demonstrates the eventual loss of mitochondria integrity in response to this drug.…”

Section: Discussionsupporting

confidence: 67%

“…The mitochondrial apoptotic pathway has been shown to play a role in proteasome inhibitor-induced apoptosis in several tumor cell models [13][14][15][16][17][18][19]. Therefore, we evaluated mitochondria integrity in DC exposed to bortezomib.…”

Section: Mitochondrial Damage In Response To Bortezomib In DCmentioning

confidence: 99%

“…Dead cells were enumerated by cell staining with 5 lg/ mL PI and flow cytometry [17,53]. The percentage of specific death was calculated as follows: 100 Â (experimental sample (%) -spontaneous sample (%)/100% -spontaneous sample (%)).…”

Section: Cell Viability Assaysmentioning

confidence: 99%

“…How proteasome inhibition translates into a potent cytotoxic effect in tumor cells is not fully understood, even though inhibition of NF-jB and deregulated expression of p53, caspases, Bcl-2 family members, CDC25 family proteins and cyclins were all proposed to be relevant in this context [1,2]. Ultimately, deregulated protein turnover by proteasome inhibition leads to activation of the intrinsic apoptotic pathway as shown by mitochondria dysfunction, production of reactive oxygen species, and endoplasmic reticulum stress, which have all been observed in response to these drugs [13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…However, lymphopenia was reported in some of the clinical studies carried out to date [4, 6,7] and may be related to inhibition of intracellular signaling pathways and/or to a direct pro-apoptotic effect of bortezomib in normal and malignant lymphocytes [17, 20, 22, 26, and A.N., unpublished observations]. On the other hand, proteasome inhibitors were shown to delay neutrophil apoptosis by favoring accumulation of the anti-apoptotic factor Mcl-1 [17,27]. Thus, it is speculated that, in some context, proteasome inhibitors may even propagate inflammatory or immune responses by preventing elimination of activated effector cells.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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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.

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Section: Discussionsupporting

confidence: 67%

Section: Mitochondrial Damage In Response To Bortezomib In DCmentioning

confidence: 99%

Section: Cell Viability Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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Proteasome inhibition activates the mitochondrial pathway of apoptosis in human CD4⁺ T cells

Berges

Haberstock

Fuchs

et al. 2009

J of Cellular Biochemistry

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We have previously shown that inhibition of the proteolytic activity of the proteasome induces apoptosis and suppresses essential functions of activated human CD4(+) T cells, and we report now the detailed mechanisms of apoptosis following proteasome inhibition in these cells. Here we show that proteasome inhibition by bortezomib activates the mitochondrial pathway of apoptosis in activated CD4(+) T cells by disrupting the equilibrium of pro-apoptotic and anti-apoptotic proteins at the outer mitochondrial membrane (OMM) and by inducing the generation of reactive oxygen species (ROS). Proteasome inhibition leads to accumulation of pro-apoptotic proteins PUMA, Noxa, Bim and p53 at the OMM. This event provokes mitochondrial translocation of activated Bax and Bak homodimers, which induce loss of mitochondrial membrane potential (DeltaPsim). Breakdown of DeltaPsim is followed by rapid release of pro-apoptotic Smac/DIABLO and HtrA2 from mitochondria, whereas release of cytochrome c and AIF is delayed. Cytoplasmic Smac/DIABLO and HtrA2 antagonize IAP-mediated inhibition of partially activated caspases, leading to premature activation of caspase-3 followed by activation of caspase-9. Our data show that proteasome inhibition triggers the mitochondrial pathway of apoptosis by activating mutually independent apoptotic pathways. These results provide novel insights into the mechanisms of apoptosis induced by proteasome inhibition in activated T cells and underscore the future use of proteasome inhibitors for immunosuppression.

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Resistance to Anti-Cancer Therapeutics

Woyach

2019

Precision Cancer Medicine

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Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis

Cited by 108 publications

References 36 publications

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

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

Proteasome inhibition activates the mitochondrial pathway of apoptosis in human CD4⁺ T cells

Resistance to Anti-Cancer Therapeutics

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Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis

Cited by 108 publications

References 36 publications

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

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

Proteasome inhibition activates the mitochondrial pathway of apoptosis in human CD4+ T cells

Resistance to Anti-Cancer Therapeutics

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Proteasome inhibition activates the mitochondrial pathway of apoptosis in human CD4⁺ T cells