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Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma
Extracellular vesicles (EVs) are lipid-based nanosized particles that convey biological material from donor to recipient cells. EVs play key roles in glioblastoma progression because glioblastoma stem-like cells (GSCs) release pro-oncogenic, pro-angiogenic, and pro-inflammatory EVs. However, the mol...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9519628/ https://www.ncbi.nlm.nih.gov/pubmed/36185361 http://dx.doi.org/10.1016/j.isci.2022.105118 |
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author | André-Grégoire, Gwennan Maghe, Clément Douanne, Tiphaine Rosińska, Sara Spinelli, Fiorella Thys, An Trillet, Kilian Jacobs, Kathryn A. Ballu, Cyndie Dupont, Aurélien Lyne, Anne-Marie Cavalli, Florence M.G. Busnelli, Ignacio Hyenne, Vincent Goetz, Jacky G. Bidère, Nicolas Gavard, Julie |
author_facet | André-Grégoire, Gwennan Maghe, Clément Douanne, Tiphaine Rosińska, Sara Spinelli, Fiorella Thys, An Trillet, Kilian Jacobs, Kathryn A. Ballu, Cyndie Dupont, Aurélien Lyne, Anne-Marie Cavalli, Florence M.G. Busnelli, Ignacio Hyenne, Vincent Goetz, Jacky G. Bidère, Nicolas Gavard, Julie |
author_sort | André-Grégoire, Gwennan |
collection | PubMed |
description | Extracellular vesicles (EVs) are lipid-based nanosized particles that convey biological material from donor to recipient cells. EVs play key roles in glioblastoma progression because glioblastoma stem-like cells (GSCs) release pro-oncogenic, pro-angiogenic, and pro-inflammatory EVs. However, the molecular basis of EV release remains poorly understood. Here, we report the identification of the pseudokinase MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of EVs in GSCs. We find that genetic, protein, and pharmacological targeting of MLKL alters intracellular trafficking and EV release, and reduces GSC expansion. Nevertheless, this function ascribed to MLKL appears independent of its role during necroptosis. In vivo, pharmacological inhibition of MLKL reduces the tumor burden and the level of plasmatic EVs. This work highlights the necroptosis-independent role of MLKL in vesicle release and suggests that interfering with EVs is a promising therapeutic option to sensitize glioblastoma cells. |
format | Online Article Text |
id | pubmed-9519628 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-95196282022-09-30 Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma André-Grégoire, Gwennan Maghe, Clément Douanne, Tiphaine Rosińska, Sara Spinelli, Fiorella Thys, An Trillet, Kilian Jacobs, Kathryn A. Ballu, Cyndie Dupont, Aurélien Lyne, Anne-Marie Cavalli, Florence M.G. Busnelli, Ignacio Hyenne, Vincent Goetz, Jacky G. Bidère, Nicolas Gavard, Julie iScience Article Extracellular vesicles (EVs) are lipid-based nanosized particles that convey biological material from donor to recipient cells. EVs play key roles in glioblastoma progression because glioblastoma stem-like cells (GSCs) release pro-oncogenic, pro-angiogenic, and pro-inflammatory EVs. However, the molecular basis of EV release remains poorly understood. Here, we report the identification of the pseudokinase MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of EVs in GSCs. We find that genetic, protein, and pharmacological targeting of MLKL alters intracellular trafficking and EV release, and reduces GSC expansion. Nevertheless, this function ascribed to MLKL appears independent of its role during necroptosis. In vivo, pharmacological inhibition of MLKL reduces the tumor burden and the level of plasmatic EVs. This work highlights the necroptosis-independent role of MLKL in vesicle release and suggests that interfering with EVs is a promising therapeutic option to sensitize glioblastoma cells. Elsevier 2022-09-13 /pmc/articles/PMC9519628/ /pubmed/36185361 http://dx.doi.org/10.1016/j.isci.2022.105118 Text en © 2022 The Author(s) https://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 André-Grégoire, Gwennan Maghe, Clément Douanne, Tiphaine Rosińska, Sara Spinelli, Fiorella Thys, An Trillet, Kilian Jacobs, Kathryn A. Ballu, Cyndie Dupont, Aurélien Lyne, Anne-Marie Cavalli, Florence M.G. Busnelli, Ignacio Hyenne, Vincent Goetz, Jacky G. Bidère, Nicolas Gavard, Julie Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma |
title | Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma |
title_full | Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma |
title_fullStr | Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma |
title_full_unstemmed | Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma |
title_short | Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma |
title_sort | inhibition of the pseudokinase mlkl alters extracellular vesicle release and reduces tumor growth in glioblastoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9519628/ https://www.ncbi.nlm.nih.gov/pubmed/36185361 http://dx.doi.org/10.1016/j.isci.2022.105118 |
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