Cargando…
Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism
Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR i...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588853/ https://www.ncbi.nlm.nih.gov/pubmed/33134898 http://dx.doi.org/10.1016/j.isci.2020.101668 |
_version_ | 1783600448565936128 |
---|---|
author | Bowler, Elizabeth Skwarska, Anna Wilson, Joseph D. Ramachandran, Shaliny Bolland, Hannah Easton, Alistair Ostheimer, Christian Hwang, Ming-Shih Leszczynska, Katarzyna B. Conway, Stuart J. Hammond, Ester M. |
author_facet | Bowler, Elizabeth Skwarska, Anna Wilson, Joseph D. Ramachandran, Shaliny Bolland, Hannah Easton, Alistair Ostheimer, Christian Hwang, Ming-Shih Leszczynska, Katarzyna B. Conway, Stuart J. Hammond, Ester M. |
author_sort | Bowler, Elizabeth |
collection | PubMed |
description | Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy. |
format | Online Article Text |
id | pubmed-7588853 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-75888532020-10-30 Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism Bowler, Elizabeth Skwarska, Anna Wilson, Joseph D. Ramachandran, Shaliny Bolland, Hannah Easton, Alistair Ostheimer, Christian Hwang, Ming-Shih Leszczynska, Katarzyna B. Conway, Stuart J. Hammond, Ester M. iScience Article Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy. Elsevier 2020-10-14 /pmc/articles/PMC7588853/ /pubmed/33134898 http://dx.doi.org/10.1016/j.isci.2020.101668 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Bowler, Elizabeth Skwarska, Anna Wilson, Joseph D. Ramachandran, Shaliny Bolland, Hannah Easton, Alistair Ostheimer, Christian Hwang, Ming-Shih Leszczynska, Katarzyna B. Conway, Stuart J. Hammond, Ester M. Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
title | Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
title_full | Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
title_fullStr | Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
title_full_unstemmed | Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
title_short | Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism |
title_sort | pharmacological inhibition of atr can block autophagy through an atr-independent mechanism |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588853/ https://www.ncbi.nlm.nih.gov/pubmed/33134898 http://dx.doi.org/10.1016/j.isci.2020.101668 |
work_keys_str_mv | AT bowlerelizabeth pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism AT skwarskaanna pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism AT wilsonjosephd pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism AT ramachandranshaliny pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism AT bollandhannah pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism AT eastonalistair pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism AT ostheimerchristian pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism AT hwangmingshih pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism AT leszczynskakatarzynab pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism AT conwaystuartj pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism AT hammondesterm pharmacologicalinhibitionofatrcanblockautophagythroughanatrindependentmechanism |