Cargando…
Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells
FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome‐wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses fou...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9449593/ https://www.ncbi.nlm.nih.gov/pubmed/35861150 http://dx.doi.org/10.15252/emmm.202215855 |
_version_ | 1784784335829729280 |
---|---|
author | Sanchez‐Burgos, Laura Navarro‐González, Belén García‐Martín, Santiago Sirozh, Oleksandra Mota‐Pino, Jorge Fueyo‐Marcos, Elena Tejero, Héctor Antón, Marta Elena Murga, Matilde Al‐Shahrour, Fátima Fernandez‐Capetillo, Oscar |
author_facet | Sanchez‐Burgos, Laura Navarro‐González, Belén García‐Martín, Santiago Sirozh, Oleksandra Mota‐Pino, Jorge Fueyo‐Marcos, Elena Tejero, Héctor Antón, Marta Elena Murga, Matilde Al‐Shahrour, Fátima Fernandez‐Capetillo, Oscar |
author_sort | Sanchez‐Burgos, Laura |
collection | PubMed |
description | FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome‐wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses found an upregulation of mitochondrial factors as a hallmark of FBXW7 deficiency, which has been previously linked to chemotherapy resistance. Despite this increased expression of mitochondrial factors, functional analyses revealed that mitochondria are under stress, and genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7‐deficient cells. Mechanistically, the toxicity of therapies targeting mitochondrial translation such as the antibiotic tigecycline relates to the activation of the integrated stress response (ISR) in a GCN2 kinase‐dependent manner. Furthermore, the discovery of additional drugs that are toxic for FBXW7‐deficient cells showed that all of them unexpectedly activate a GCN2‐dependent ISR regardless of their accepted mechanism of action. Our study reveals that while one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, it renders cells vulnerable to ISR‐activating drugs. |
format | Online Article Text |
id | pubmed-9449593 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94495932022-09-09 Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells Sanchez‐Burgos, Laura Navarro‐González, Belén García‐Martín, Santiago Sirozh, Oleksandra Mota‐Pino, Jorge Fueyo‐Marcos, Elena Tejero, Héctor Antón, Marta Elena Murga, Matilde Al‐Shahrour, Fátima Fernandez‐Capetillo, Oscar EMBO Mol Med Articles FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome‐wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses found an upregulation of mitochondrial factors as a hallmark of FBXW7 deficiency, which has been previously linked to chemotherapy resistance. Despite this increased expression of mitochondrial factors, functional analyses revealed that mitochondria are under stress, and genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7‐deficient cells. Mechanistically, the toxicity of therapies targeting mitochondrial translation such as the antibiotic tigecycline relates to the activation of the integrated stress response (ISR) in a GCN2 kinase‐dependent manner. Furthermore, the discovery of additional drugs that are toxic for FBXW7‐deficient cells showed that all of them unexpectedly activate a GCN2‐dependent ISR regardless of their accepted mechanism of action. Our study reveals that while one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, it renders cells vulnerable to ISR‐activating drugs. John Wiley and Sons Inc. 2022-07-21 /pmc/articles/PMC9449593/ /pubmed/35861150 http://dx.doi.org/10.15252/emmm.202215855 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Sanchez‐Burgos, Laura Navarro‐González, Belén García‐Martín, Santiago Sirozh, Oleksandra Mota‐Pino, Jorge Fueyo‐Marcos, Elena Tejero, Héctor Antón, Marta Elena Murga, Matilde Al‐Shahrour, Fátima Fernandez‐Capetillo, Oscar Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
title | Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
title_full | Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
title_fullStr | Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
title_full_unstemmed | Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
title_short | Activation of the integrated stress response is a vulnerability for multidrug‐resistant FBXW7‐deficient cells |
title_sort | activation of the integrated stress response is a vulnerability for multidrug‐resistant fbxw7‐deficient cells |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9449593/ https://www.ncbi.nlm.nih.gov/pubmed/35861150 http://dx.doi.org/10.15252/emmm.202215855 |
work_keys_str_mv | AT sanchezburgoslaura activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells AT navarrogonzalezbelen activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells AT garciamartinsantiago activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells AT sirozholeksandra activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells AT motapinojorge activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells AT fueyomarcoselena activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells AT tejerohector activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells AT antonmartaelena activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells AT murgamatilde activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells AT alshahrourfatima activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells AT fernandezcapetillooscar activationoftheintegratedstressresponseisavulnerabilityformultidrugresistantfbxw7deficientcells |