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VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells

Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the accumulation of undifferentiated white blood cells (blasts) in the bone marrow. Valosin-containing protein (VCP) is an abundant molecular chaperone that extracts ubiquitylated substrates from protein complexes and cellul...

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Autores principales: Szczęśniak, Paweł P., Heidelberger, Jan B., Serve, Hubert, Beli, Petra, Wagner, Sebastian A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986003/
https://www.ncbi.nlm.nih.gov/pubmed/35385564
http://dx.doi.org/10.1371/journal.pone.0266478
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author Szczęśniak, Paweł P.
Heidelberger, Jan B.
Serve, Hubert
Beli, Petra
Wagner, Sebastian A.
author_facet Szczęśniak, Paweł P.
Heidelberger, Jan B.
Serve, Hubert
Beli, Petra
Wagner, Sebastian A.
author_sort Szczęśniak, Paweł P.
collection PubMed
description Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the accumulation of undifferentiated white blood cells (blasts) in the bone marrow. Valosin-containing protein (VCP) is an abundant molecular chaperone that extracts ubiquitylated substrates from protein complexes and cellular compartments prior to their degradation by the proteasome. We found that treatment of AML cell lines with the VCP inhibitor CB-5083 leads to an accumulation of ubiquitylated proteins, activation of unfolded protein response (UPR) and apoptosis. Using quantitative mass spectrometry-based proteomics we assessed the effects of VCP inhibition on the cellular ubiquitin-modified proteome. We could further show that CB-5083 decreases the survival of the AML cell lines THP-1 and MV4-11 in a concentration-dependent manner, and acts synergistically with the antimetabolite cytarabine and the BH3-mimetic venetoclax. Finally, we showed that prolonged treatment of AML cells with CB-5083 leads to development of resistance mediated by mutations in VCP. Taken together, inhibition of VCP leads to a lethal unfolded protein response in AML cells and might be a relevant therapeutic strategy for treatment of AML, particularly when combined with other drugs. The toxicity and development of resistance possibly limit the utility of VCP inhibitors and have to be further explored in animal models and clinical trials.
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spelling pubmed-89860032022-04-07 VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells Szczęśniak, Paweł P. Heidelberger, Jan B. Serve, Hubert Beli, Petra Wagner, Sebastian A. PLoS One Research Article Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the accumulation of undifferentiated white blood cells (blasts) in the bone marrow. Valosin-containing protein (VCP) is an abundant molecular chaperone that extracts ubiquitylated substrates from protein complexes and cellular compartments prior to their degradation by the proteasome. We found that treatment of AML cell lines with the VCP inhibitor CB-5083 leads to an accumulation of ubiquitylated proteins, activation of unfolded protein response (UPR) and apoptosis. Using quantitative mass spectrometry-based proteomics we assessed the effects of VCP inhibition on the cellular ubiquitin-modified proteome. We could further show that CB-5083 decreases the survival of the AML cell lines THP-1 and MV4-11 in a concentration-dependent manner, and acts synergistically with the antimetabolite cytarabine and the BH3-mimetic venetoclax. Finally, we showed that prolonged treatment of AML cells with CB-5083 leads to development of resistance mediated by mutations in VCP. Taken together, inhibition of VCP leads to a lethal unfolded protein response in AML cells and might be a relevant therapeutic strategy for treatment of AML, particularly when combined with other drugs. The toxicity and development of resistance possibly limit the utility of VCP inhibitors and have to be further explored in animal models and clinical trials. Public Library of Science 2022-04-06 /pmc/articles/PMC8986003/ /pubmed/35385564 http://dx.doi.org/10.1371/journal.pone.0266478 Text en © 2022 Szczęśniak et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Szczęśniak, Paweł P.
Heidelberger, Jan B.
Serve, Hubert
Beli, Petra
Wagner, Sebastian A.
VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells
title VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells
title_full VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells
title_fullStr VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells
title_full_unstemmed VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells
title_short VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells
title_sort vcp inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986003/
https://www.ncbi.nlm.nih.gov/pubmed/35385564
http://dx.doi.org/10.1371/journal.pone.0266478
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