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A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors

We here conducted an image-based chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. None of the compounds up-regulated translation, which could be due to the screen being performed in cancer cells gro...

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Autores principales: Corman, Alba, Kanellis, Dimitris C., Michalska, Patrycja, Häggblad, Maria, Lafarga, Vanesa, Bartek, Jiri, Carreras-Puigvert, Jordi, Fernandez-Capetillo, Oscar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183993/
https://www.ncbi.nlm.nih.gov/pubmed/34033645
http://dx.doi.org/10.1371/journal.pbio.3001263
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author Corman, Alba
Kanellis, Dimitris C.
Michalska, Patrycja
Häggblad, Maria
Lafarga, Vanesa
Bartek, Jiri
Carreras-Puigvert, Jordi
Fernandez-Capetillo, Oscar
author_facet Corman, Alba
Kanellis, Dimitris C.
Michalska, Patrycja
Häggblad, Maria
Lafarga, Vanesa
Bartek, Jiri
Carreras-Puigvert, Jordi
Fernandez-Capetillo, Oscar
author_sort Corman, Alba
collection PubMed
description We here conducted an image-based chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. None of the compounds up-regulated translation, which could be due to the screen being performed in cancer cells grown in full media where translation is already present at very high levels. Regarding translation down-regulators, and consistent with current knowledge, inhibitors of the mechanistic target of rapamycin (mTOR) signaling pathway were the most represented class. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically, this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum (ER), which activates the integrated stress response (ISR) and contributes to the toxicity of SPHK inhibitors. Surprisingly, the toxicity and activation of the ISR triggered by 2 independent SPHK inhibitors, SKI-II and ABC294640, the latter in clinical trials, are also observed in cells lacking SPHK1 and SPHK2. In summary, our study provides a useful resource on the effects of medically used drugs on translation, identified compounds capable of reducing translation independently of mTOR and has revealed that the cytotoxic properties of SPHK inhibitors being developed as anticancer agents are independent of SPHKs.
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spelling pubmed-81839932021-06-21 A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors Corman, Alba Kanellis, Dimitris C. Michalska, Patrycja Häggblad, Maria Lafarga, Vanesa Bartek, Jiri Carreras-Puigvert, Jordi Fernandez-Capetillo, Oscar PLoS Biol Research Article We here conducted an image-based chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. None of the compounds up-regulated translation, which could be due to the screen being performed in cancer cells grown in full media where translation is already present at very high levels. Regarding translation down-regulators, and consistent with current knowledge, inhibitors of the mechanistic target of rapamycin (mTOR) signaling pathway were the most represented class. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically, this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum (ER), which activates the integrated stress response (ISR) and contributes to the toxicity of SPHK inhibitors. Surprisingly, the toxicity and activation of the ISR triggered by 2 independent SPHK inhibitors, SKI-II and ABC294640, the latter in clinical trials, are also observed in cells lacking SPHK1 and SPHK2. In summary, our study provides a useful resource on the effects of medically used drugs on translation, identified compounds capable of reducing translation independently of mTOR and has revealed that the cytotoxic properties of SPHK inhibitors being developed as anticancer agents are independent of SPHKs. Public Library of Science 2021-05-25 /pmc/articles/PMC8183993/ /pubmed/34033645 http://dx.doi.org/10.1371/journal.pbio.3001263 Text en © 2021 Corman et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Corman, Alba
Kanellis, Dimitris C.
Michalska, Patrycja
Häggblad, Maria
Lafarga, Vanesa
Bartek, Jiri
Carreras-Puigvert, Jordi
Fernandez-Capetillo, Oscar
A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors
title A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors
title_full A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors
title_fullStr A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors
title_full_unstemmed A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors
title_short A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors
title_sort chemical screen for modulators of mrna translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183993/
https://www.ncbi.nlm.nih.gov/pubmed/34033645
http://dx.doi.org/10.1371/journal.pbio.3001263
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