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Robustness of the Autophagy Pathway to Somatic Copy Number Losses

Autophagy allows cells to temporarily tolerate energy stress by replenishing critical metabolites through self-digestion, thereby attenuating the cytotoxic effects of anticancer drugs that target tumor metabolism. Autophagy defects could therefore mark a metabolically vulnerable cancer state and ope...

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Autores principales: Polo, Pierfrancesco, Gremke, Niklas, Stiewe, Thorsten, Wanzel, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9179279/
https://www.ncbi.nlm.nih.gov/pubmed/35681458
http://dx.doi.org/10.3390/cells11111762
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author Polo, Pierfrancesco
Gremke, Niklas
Stiewe, Thorsten
Wanzel, Michael
author_facet Polo, Pierfrancesco
Gremke, Niklas
Stiewe, Thorsten
Wanzel, Michael
author_sort Polo, Pierfrancesco
collection PubMed
description Autophagy allows cells to temporarily tolerate energy stress by replenishing critical metabolites through self-digestion, thereby attenuating the cytotoxic effects of anticancer drugs that target tumor metabolism. Autophagy defects could therefore mark a metabolically vulnerable cancer state and open a therapeutic window. While mutations of autophagy genes (ATGs) are notably rare in cancer, haploinsufficiency network analyses across many cancers have shown that the autophagy pathway is frequently hit by somatic copy number losses of ATGs such as MAP1LC3B/ATG8F (LC3), BECN1/ATG6 (Beclin-1), and ATG10. Here, we used CRISPR/Cas9 technology to delete increasing numbers of copies of one or more of these ATGs in non-small cell lung cancer cells and examined the effects on sensitivity to compounds targeting aerobic glycolysis, a hallmark of cancer metabolism. Whereas the complete knockout of one ATG blocked autophagy and led to profound metabolic vulnerability, this was not the case for combinations of different nonhomozygous deletions. In cancer patients, the effect of ATG copy number loss was blunted at the protein level and did not lead to the accumulation of p62 as a sign of reduced autophagic flux. Thus, the autophagy pathway is shown to be markedly robust and resilient, even with the concomitant copy number loss of key autophagy genes.
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spelling pubmed-91792792022-06-10 Robustness of the Autophagy Pathway to Somatic Copy Number Losses Polo, Pierfrancesco Gremke, Niklas Stiewe, Thorsten Wanzel, Michael Cells Article Autophagy allows cells to temporarily tolerate energy stress by replenishing critical metabolites through self-digestion, thereby attenuating the cytotoxic effects of anticancer drugs that target tumor metabolism. Autophagy defects could therefore mark a metabolically vulnerable cancer state and open a therapeutic window. While mutations of autophagy genes (ATGs) are notably rare in cancer, haploinsufficiency network analyses across many cancers have shown that the autophagy pathway is frequently hit by somatic copy number losses of ATGs such as MAP1LC3B/ATG8F (LC3), BECN1/ATG6 (Beclin-1), and ATG10. Here, we used CRISPR/Cas9 technology to delete increasing numbers of copies of one or more of these ATGs in non-small cell lung cancer cells and examined the effects on sensitivity to compounds targeting aerobic glycolysis, a hallmark of cancer metabolism. Whereas the complete knockout of one ATG blocked autophagy and led to profound metabolic vulnerability, this was not the case for combinations of different nonhomozygous deletions. In cancer patients, the effect of ATG copy number loss was blunted at the protein level and did not lead to the accumulation of p62 as a sign of reduced autophagic flux. Thus, the autophagy pathway is shown to be markedly robust and resilient, even with the concomitant copy number loss of key autophagy genes. MDPI 2022-05-27 /pmc/articles/PMC9179279/ /pubmed/35681458 http://dx.doi.org/10.3390/cells11111762 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Polo, Pierfrancesco
Gremke, Niklas
Stiewe, Thorsten
Wanzel, Michael
Robustness of the Autophagy Pathway to Somatic Copy Number Losses
title Robustness of the Autophagy Pathway to Somatic Copy Number Losses
title_full Robustness of the Autophagy Pathway to Somatic Copy Number Losses
title_fullStr Robustness of the Autophagy Pathway to Somatic Copy Number Losses
title_full_unstemmed Robustness of the Autophagy Pathway to Somatic Copy Number Losses
title_short Robustness of the Autophagy Pathway to Somatic Copy Number Losses
title_sort robustness of the autophagy pathway to somatic copy number losses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9179279/
https://www.ncbi.nlm.nih.gov/pubmed/35681458
http://dx.doi.org/10.3390/cells11111762
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