Molecular sequelae of proteasome inhibition in human multiple myeloma cells

Mitsiades, Nicholas; Mitsiades, Constantine S.; Poulaki, Vassiliki; Chauhan, Dharminder; Fanourakis, Galinos; Gu, Xuesong; Bailey, Charles C.; Joseph, Marie; Libermann, Towia A.; Treon, Steven P.; Munshi, Nikhil C.; Richardson, Paul G.; Hideshima, Teru; Anderson, Kenneth C.

doi:10.1073/pnas.202445099

Cited by 696 publications

(633 citation statements)

References 54 publications

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“…These paradigms demonstrate that the proteome composition upon exposure to proteasome inhibitors is not only affected by changes on a transcriptional level as can be determined by microarray experiments, but is in the first line the result of posttranslational events, such as inhibition of protein turnover and protein accumulation, modification by phosphorylation and ubiquitin conjugation as well as proteolytic processing by caspases [58,59]. To delineate critical events in cellular signaling that ultimately lead to the demise of leukemic cells by proteasome inhibitors, it is therefore essential to complement mRNA expression studies with a characterization of changes within the proteome.…”

Section: Discussionmentioning

confidence: 80%

“…Multiple myeloma cells have thus been reported to upregulate various proteasomal subunits in response to bortezomib treatment [59], which in conjunction with an altered subunit composition may result in increased overall catabolic activity by the ubiquitin proteasome pathway. Similar observations were also made in Burkitt lymphoma [62] and in vascular smooth muscle cells [63].…”

Section: Discussionmentioning

confidence: 99%

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Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI

Choi

Najafi

Safa

et al. 2008

Biochemical Pharmacology

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Proteasome inhibitors display potent anti-neoplastic and anti-angiogenic properties both in vitro and in vivo. The mechanisms, however, by which proteasome inhibitors kill tumor cells are still fairly elusive as is the molecular basis of resistance to treatment. To address these questions, we employed a high-throughput Western blotting procedure to analyze changes in a subproteome of ~800 proteins in the promyelocytic leukemia cell line HL-60 upon treatment with the proteasome inhibitor PSI (ZIle-Glu(OtBu)-Ala-Leu-aldehyde) and correlated the changes of selected target proteins with the changes in two multidrug resistant HL-60 variants. In total, 105 proteins were upregulated more than 1.5-fold after PSI treatment, while 79 proteins were downregulated. Activation of caspases-3 and -8, modulation of members of the Bcl-2 family as well as stimulation of stress signaling pathways was prominent during HL-60 apoptosis. We also identified changes in the abundance of proteins previously not known to be affected by proteasome inhibitors. In contrast, two multidrug resistant HL-60 cell lines, overexpressing either MRP1 or P-glycoprotein were largely resistant to PSI-induced apoptosis and could not be resensitized by the pharmacological inhibitors of the drug efflux pumps MK571 or PSC833. Drug resistance was also independent from the upregulation of Bad. Overexpression of multidrug resistance proteins, P-glycoprotein and MRP-1 is thus not sufficient to explain resistance of HL-60 cells to treatment with proteasome inhibitor PSI, which remains more closely related to a low level of Bax expression and to the inability to activate JNK. Alternative routes to the acquisition of resistance to PSI have therefore to be considered. Classification(1) Antibiotics and Chemotherapeutics

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI

Choi

Najafi

Safa

et al. 2008

Biochemical Pharmacology

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“…Consistent with this, monoclonal antibodies to CD40 block CD40L-induced NF-kB activation as well as IL-6 and VEGF secretion in cocultures of multiple myeloma cells and bone marrowderived stromal cells (Tai et al, 2005). Interestingly, multiple myeloma is currently treated with compounds that can block NF-kB activation (Mitsiades et al, 2002a) (see below).…”

Section: Nf-kb In Hematologic Malignanciesmentioning

confidence: 78%

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

2006

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“…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%

“…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%

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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Molecular sequelae of proteasome inhibition in human multiple myeloma cells

Cited by 696 publications

References 54 publications

Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI

Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

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

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