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The Deubiquitinase Inhibitor b-AP15 and Its Effect on Phenotype and Function of Monocyte-Derived Dendritic Cells

The ubiquitin-proteasome system is elementary for cellular protein degradation and gained rising attention as a new target for cancer therapy due to promising clinical trials with bortezomib, the first-in class proteasome inhibitor meanwhile approved for multiple myeloma and mantle cell lymphoma. Bo...

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Autores principales: Schmidt, Moritz, Altdörfer, Vanessa, Schnitte, Sarah, Fuchs, Alexander Rolf, Kropp, Korbinian Nepomuk, Maurer, Stefanie, Müller, Martin Rudolf, Salih, Helmut Rainer, Rittig, Susanne Malaika, Grünebach, Frank, Dörfel, Daniela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538843/
https://www.ncbi.nlm.nih.gov/pubmed/31132676
http://dx.doi.org/10.1016/j.neo.2019.03.001
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author Schmidt, Moritz
Altdörfer, Vanessa
Schnitte, Sarah
Fuchs, Alexander Rolf
Kropp, Korbinian Nepomuk
Maurer, Stefanie
Müller, Martin Rudolf
Salih, Helmut Rainer
Rittig, Susanne Malaika
Grünebach, Frank
Dörfel, Daniela
author_facet Schmidt, Moritz
Altdörfer, Vanessa
Schnitte, Sarah
Fuchs, Alexander Rolf
Kropp, Korbinian Nepomuk
Maurer, Stefanie
Müller, Martin Rudolf
Salih, Helmut Rainer
Rittig, Susanne Malaika
Grünebach, Frank
Dörfel, Daniela
author_sort Schmidt, Moritz
collection PubMed
description The ubiquitin-proteasome system is elementary for cellular protein degradation and gained rising attention as a new target for cancer therapy due to promising clinical trials with bortezomib, the first-in class proteasome inhibitor meanwhile approved for multiple myeloma and mantle cell lymphoma. Both bortezomib and next-generation proteasome inhibitors mediate their effects by targeting the 20S core particle of the 26S proteasome. The novel small molecule inhibitor b-AP15 affects upstream elements of the ubiquitin-proteasome cascade by suppressing the deubiquitinase activity of both proteasomal regulatory 19S subunits and showed promising anticancer activity in preclinical models. Nonetheless, effects of inhibitors on the ubiquitin-proteasome system are not exclusively restricted to malignant cells: alteration of natural killer cell-mediated immune responses had already been described for drugs targeting either 19S or 20S proteasomal subunits. Moreover, it has been shown that bortezomib impairs dendritic cell (DC) phenotype and function at different levels. In the present study, we comparatively analyzed effects of bortezomib and b-AP15 on monocyte-derived DCs. In line with previous results, bortezomib exposure impaired maturation, antigen uptake, migration, cytokine secretion and immunostimulation, whereas treatment with b-AP15 had no compromising effects on these DC features. Our findings warrant the further investigation of b-AP15 as an alternative to clinically approved proteasome inhibitors in the therapy of malignancies, especially in the context of combinatorial treatment with DC-based immunotherapies.
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spelling pubmed-65388432019-06-03 The Deubiquitinase Inhibitor b-AP15 and Its Effect on Phenotype and Function of Monocyte-Derived Dendritic Cells Schmidt, Moritz Altdörfer, Vanessa Schnitte, Sarah Fuchs, Alexander Rolf Kropp, Korbinian Nepomuk Maurer, Stefanie Müller, Martin Rudolf Salih, Helmut Rainer Rittig, Susanne Malaika Grünebach, Frank Dörfel, Daniela Neoplasia Original article The ubiquitin-proteasome system is elementary for cellular protein degradation and gained rising attention as a new target for cancer therapy due to promising clinical trials with bortezomib, the first-in class proteasome inhibitor meanwhile approved for multiple myeloma and mantle cell lymphoma. Both bortezomib and next-generation proteasome inhibitors mediate their effects by targeting the 20S core particle of the 26S proteasome. The novel small molecule inhibitor b-AP15 affects upstream elements of the ubiquitin-proteasome cascade by suppressing the deubiquitinase activity of both proteasomal regulatory 19S subunits and showed promising anticancer activity in preclinical models. Nonetheless, effects of inhibitors on the ubiquitin-proteasome system are not exclusively restricted to malignant cells: alteration of natural killer cell-mediated immune responses had already been described for drugs targeting either 19S or 20S proteasomal subunits. Moreover, it has been shown that bortezomib impairs dendritic cell (DC) phenotype and function at different levels. In the present study, we comparatively analyzed effects of bortezomib and b-AP15 on monocyte-derived DCs. In line with previous results, bortezomib exposure impaired maturation, antigen uptake, migration, cytokine secretion and immunostimulation, whereas treatment with b-AP15 had no compromising effects on these DC features. Our findings warrant the further investigation of b-AP15 as an alternative to clinically approved proteasome inhibitors in the therapy of malignancies, especially in the context of combinatorial treatment with DC-based immunotherapies. Neoplasia Press 2019-05-25 /pmc/articles/PMC6538843/ /pubmed/31132676 http://dx.doi.org/10.1016/j.neo.2019.03.001 Text en © 2019 Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original article
Schmidt, Moritz
Altdörfer, Vanessa
Schnitte, Sarah
Fuchs, Alexander Rolf
Kropp, Korbinian Nepomuk
Maurer, Stefanie
Müller, Martin Rudolf
Salih, Helmut Rainer
Rittig, Susanne Malaika
Grünebach, Frank
Dörfel, Daniela
The Deubiquitinase Inhibitor b-AP15 and Its Effect on Phenotype and Function of Monocyte-Derived Dendritic Cells
title The Deubiquitinase Inhibitor b-AP15 and Its Effect on Phenotype and Function of Monocyte-Derived Dendritic Cells
title_full The Deubiquitinase Inhibitor b-AP15 and Its Effect on Phenotype and Function of Monocyte-Derived Dendritic Cells
title_fullStr The Deubiquitinase Inhibitor b-AP15 and Its Effect on Phenotype and Function of Monocyte-Derived Dendritic Cells
title_full_unstemmed The Deubiquitinase Inhibitor b-AP15 and Its Effect on Phenotype and Function of Monocyte-Derived Dendritic Cells
title_short The Deubiquitinase Inhibitor b-AP15 and Its Effect on Phenotype and Function of Monocyte-Derived Dendritic Cells
title_sort deubiquitinase inhibitor b-ap15 and its effect on phenotype and function of monocyte-derived dendritic cells
topic Original article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538843/
https://www.ncbi.nlm.nih.gov/pubmed/31132676
http://dx.doi.org/10.1016/j.neo.2019.03.001
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