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Quiescent fibroblasts are protected from proteasome inhibition–mediated toxicity

Proteasome inhibition is used as a treatment strategy for multiple types of cancers. Although proteasome inhibition can induce apoptotic cell death in actively proliferating cells, it is less effective in quiescent cells. In this study, we used primary human fibroblasts as a model system to explore...

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Autores principales: Legesse-Miller, Aster, Raitman, Irene, Haley, Erin M., Liao, Albert, Sun, Lova L., Wang, David J., Krishnan, Nithya, Lemons, Johanna M. S., Suh, Eric J., Johnson, Elizabeth L., Lund, Benjamin A., Coller, Hilary A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442405/
https://www.ncbi.nlm.nih.gov/pubmed/22875985
http://dx.doi.org/10.1091/mbc.E12-03-0192
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author Legesse-Miller, Aster
Raitman, Irene
Haley, Erin M.
Liao, Albert
Sun, Lova L.
Wang, David J.
Krishnan, Nithya
Lemons, Johanna M. S.
Suh, Eric J.
Johnson, Elizabeth L.
Lund, Benjamin A.
Coller, Hilary A.
author_facet Legesse-Miller, Aster
Raitman, Irene
Haley, Erin M.
Liao, Albert
Sun, Lova L.
Wang, David J.
Krishnan, Nithya
Lemons, Johanna M. S.
Suh, Eric J.
Johnson, Elizabeth L.
Lund, Benjamin A.
Coller, Hilary A.
author_sort Legesse-Miller, Aster
collection PubMed
description Proteasome inhibition is used as a treatment strategy for multiple types of cancers. Although proteasome inhibition can induce apoptotic cell death in actively proliferating cells, it is less effective in quiescent cells. In this study, we used primary human fibroblasts as a model system to explore the link between the proliferative state of a cell and proteasome inhibition–mediated cell death. We found that proliferating and quiescent fibroblasts have strikingly different responses to MG132, a proteasome inhibitor; proliferating cells rapidly apoptosed, whereas quiescent cells maintained viability. Moreover, MG132 treatment of proliferating fibroblasts led to increased superoxide anion levels, juxtanuclear accumulation of ubiquitin- and p62/SQSTM1-positive protein aggregates, and apoptotic cell death, whereas MG132-treated quiescent cells displayed fewer juxtanuclear protein aggregates, less apoptosis, and higher levels of mitochondrial superoxide dismutase. In both cell states, reducing reactive oxygen species with N-acetylcysteine lessened protein aggregation and decreased apoptosis, suggesting that protein aggregation promotes apoptosis. In contrast, increasing cellular superoxide levels with 2-methoxyestradiol treatment or inhibition of autophagy/lysosomal pathways with bafilomycin A1 sensitized serum-starved quiescent cells to MG132-induced apoptosis. Thus, antioxidant defenses and the autophagy/lysosomal pathway protect serum-starved quiescent fibroblasts from proteasome inhibition–induced cytotoxicity.
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spelling pubmed-34424052012-11-30 Quiescent fibroblasts are protected from proteasome inhibition–mediated toxicity Legesse-Miller, Aster Raitman, Irene Haley, Erin M. Liao, Albert Sun, Lova L. Wang, David J. Krishnan, Nithya Lemons, Johanna M. S. Suh, Eric J. Johnson, Elizabeth L. Lund, Benjamin A. Coller, Hilary A. Mol Biol Cell Articles Proteasome inhibition is used as a treatment strategy for multiple types of cancers. Although proteasome inhibition can induce apoptotic cell death in actively proliferating cells, it is less effective in quiescent cells. In this study, we used primary human fibroblasts as a model system to explore the link between the proliferative state of a cell and proteasome inhibition–mediated cell death. We found that proliferating and quiescent fibroblasts have strikingly different responses to MG132, a proteasome inhibitor; proliferating cells rapidly apoptosed, whereas quiescent cells maintained viability. Moreover, MG132 treatment of proliferating fibroblasts led to increased superoxide anion levels, juxtanuclear accumulation of ubiquitin- and p62/SQSTM1-positive protein aggregates, and apoptotic cell death, whereas MG132-treated quiescent cells displayed fewer juxtanuclear protein aggregates, less apoptosis, and higher levels of mitochondrial superoxide dismutase. In both cell states, reducing reactive oxygen species with N-acetylcysteine lessened protein aggregation and decreased apoptosis, suggesting that protein aggregation promotes apoptosis. In contrast, increasing cellular superoxide levels with 2-methoxyestradiol treatment or inhibition of autophagy/lysosomal pathways with bafilomycin A1 sensitized serum-starved quiescent cells to MG132-induced apoptosis. Thus, antioxidant defenses and the autophagy/lysosomal pathway protect serum-starved quiescent fibroblasts from proteasome inhibition–induced cytotoxicity. The American Society for Cell Biology 2012-09-15 /pmc/articles/PMC3442405/ /pubmed/22875985 http://dx.doi.org/10.1091/mbc.E12-03-0192 Text en © 2012 Legesse-Miller et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell BD; are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Legesse-Miller, Aster
Raitman, Irene
Haley, Erin M.
Liao, Albert
Sun, Lova L.
Wang, David J.
Krishnan, Nithya
Lemons, Johanna M. S.
Suh, Eric J.
Johnson, Elizabeth L.
Lund, Benjamin A.
Coller, Hilary A.
Quiescent fibroblasts are protected from proteasome inhibition–mediated toxicity
title Quiescent fibroblasts are protected from proteasome inhibition–mediated toxicity
title_full Quiescent fibroblasts are protected from proteasome inhibition–mediated toxicity
title_fullStr Quiescent fibroblasts are protected from proteasome inhibition–mediated toxicity
title_full_unstemmed Quiescent fibroblasts are protected from proteasome inhibition–mediated toxicity
title_short Quiescent fibroblasts are protected from proteasome inhibition–mediated toxicity
title_sort quiescent fibroblasts are protected from proteasome inhibition–mediated toxicity
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442405/
https://www.ncbi.nlm.nih.gov/pubmed/22875985
http://dx.doi.org/10.1091/mbc.E12-03-0192
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