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A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence

At their proliferative limit, normal cells arrest and undergo replicative senescence, displaying large cell size, flat morphology, and senescence-associated beta-galactosidase (SA-β-Gal) activity. Normal or tumor cells exposed to genotoxic stress undergo therapy-induced senescence (TIS), displaying...

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Autores principales: Flor, Amy C, Wolfgeher, Don, Wu, Ding, Kron, Stephen J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661608/
https://www.ncbi.nlm.nih.gov/pubmed/29090099
http://dx.doi.org/10.1038/cddiscovery.2017.75
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author Flor, Amy C
Wolfgeher, Don
Wu, Ding
Kron, Stephen J
author_facet Flor, Amy C
Wolfgeher, Don
Wu, Ding
Kron, Stephen J
author_sort Flor, Amy C
collection PubMed
description At their proliferative limit, normal cells arrest and undergo replicative senescence, displaying large cell size, flat morphology, and senescence-associated beta-galactosidase (SA-β-Gal) activity. Normal or tumor cells exposed to genotoxic stress undergo therapy-induced senescence (TIS), displaying a similar phenotype. Senescence is considered a DNA damage response, but cellular heterogeneity has frustrated identification of senescence-specific markers and targets. To explore the senescent cell proteome, we treated tumor cells with etoposide and enriched SA-β-Gal(HI) cells by fluorescence-activated cell sorting (FACS). The enriched TIS cells were compared to proliferating or quiescent cells by label-free quantitative LC-MS/MS proteomics and systems analysis, revealing activation of multiple lipid metabolism pathways. Senescent cells accumulated lipid droplets and imported lipid tracers, while treating proliferating cells with specific lipids induced senescence. Senescent cells also displayed increased lipid aldehydes and upregulation of aldehyde detoxifying enzymes. These results place deregulation of lipid metabolism alongside genotoxic stress as factors regulating cellular senescence.
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spelling pubmed-56616082017-10-31 A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence Flor, Amy C Wolfgeher, Don Wu, Ding Kron, Stephen J Cell Death Discov Article At their proliferative limit, normal cells arrest and undergo replicative senescence, displaying large cell size, flat morphology, and senescence-associated beta-galactosidase (SA-β-Gal) activity. Normal or tumor cells exposed to genotoxic stress undergo therapy-induced senescence (TIS), displaying a similar phenotype. Senescence is considered a DNA damage response, but cellular heterogeneity has frustrated identification of senescence-specific markers and targets. To explore the senescent cell proteome, we treated tumor cells with etoposide and enriched SA-β-Gal(HI) cells by fluorescence-activated cell sorting (FACS). The enriched TIS cells were compared to proliferating or quiescent cells by label-free quantitative LC-MS/MS proteomics and systems analysis, revealing activation of multiple lipid metabolism pathways. Senescent cells accumulated lipid droplets and imported lipid tracers, while treating proliferating cells with specific lipids induced senescence. Senescent cells also displayed increased lipid aldehydes and upregulation of aldehyde detoxifying enzymes. These results place deregulation of lipid metabolism alongside genotoxic stress as factors regulating cellular senescence. Nature Publishing Group 2017-10-30 /pmc/articles/PMC5661608/ /pubmed/29090099 http://dx.doi.org/10.1038/cddiscovery.2017.75 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Flor, Amy C
Wolfgeher, Don
Wu, Ding
Kron, Stephen J
A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence
title A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence
title_full A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence
title_fullStr A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence
title_full_unstemmed A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence
title_short A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence
title_sort signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661608/
https://www.ncbi.nlm.nih.gov/pubmed/29090099
http://dx.doi.org/10.1038/cddiscovery.2017.75
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