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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-9179279 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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