Spatial sequestration of activated-caspase 3 in aggresomes mediates resistance of neuroblastoma cell to bortezomib treatment
Abstract Neuroblastoma (NB) is the most common pediatric tumor and is currently treated by several types of therapies including chemotherapies, such as bortezomib treatment. However, resistance to bortezomib is frequently observed by mechanisms that remain to be deciphered. Bortezomib treatment lead...
| Principais autores: | , , , , , , , , , , , , , |
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| Formato: | Artigo |
| Idioma: | English |
| Publicado em: |
Nature Portfolio
2024-02-01
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| coleção: | Scientific Reports |
| Acesso em linha: | https://doi.org/10.1038/s41598-024-54140-7 |
| _version_ | 1827327905537982464 |
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| author | Kévin Berthenet Eliézer Aïmontché Sara El Mrini Johan Brière Nathalie Pion Isabelle Iacono Stéphanie Brejon Karine Monier Frédéric Catez Gabriel Ichim Valérie Combaret Hichem C. Mertani Jean-Jacques Diaz Marie Alexandra Albaret |
| author_facet | Kévin Berthenet Eliézer Aïmontché Sara El Mrini Johan Brière Nathalie Pion Isabelle Iacono Stéphanie Brejon Karine Monier Frédéric Catez Gabriel Ichim Valérie Combaret Hichem C. Mertani Jean-Jacques Diaz Marie Alexandra Albaret |
| author_sort | Kévin Berthenet |
| collection | DOAJ |
| description | Abstract Neuroblastoma (NB) is the most common pediatric tumor and is currently treated by several types of therapies including chemotherapies, such as bortezomib treatment. However, resistance to bortezomib is frequently observed by mechanisms that remain to be deciphered. Bortezomib treatment leads to caspase activation and aggresome formation. Using models of patients-derived NB cell lines with different levels of sensitivity to bortezomib, we show that the activated form of caspase 3 accumulates within aggresomes of NB resistant cells leading to an impairment of bortezomib-induced apoptosis and increased cell survival. Our findings unveil a new mechanism of resistance to chemotherapy based on an altered subcellular distribution of the executioner caspase 3. This mechanism could explain the resistance developed in NB patients treated with bortezomib, emphasizing the potential of drugs targeting aggresomes. |
| first_indexed | 2024-03-07T15:09:10Z |
| format | Article |
| id | doaj.art-788b9ca5c54648d4acf6471c8b842864 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:09:10Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-788b9ca5c54648d4acf6471c8b8428642024-03-05T18:43:46ZengNature PortfolioScientific Reports2045-23222024-02-0114111210.1038/s41598-024-54140-7Spatial sequestration of activated-caspase 3 in aggresomes mediates resistance of neuroblastoma cell to bortezomib treatmentKévin Berthenet0Eliézer Aïmontché1Sara El Mrini2Johan Brière3Nathalie Pion4Isabelle Iacono5Stéphanie Brejon6Karine Monier7Frédéric Catez8Gabriel Ichim9Valérie Combaret10Hichem C. Mertani11Jean-Jacques Diaz12Marie Alexandra Albaret13Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonDepartment of Translational Research and Innovation, Centre Léon BérardDepartment of Translational Research and Innovation, Centre Léon BérardUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonDepartment of Translational Research and Innovation, Centre Léon BérardUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonUniv Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of LyonAbstract Neuroblastoma (NB) is the most common pediatric tumor and is currently treated by several types of therapies including chemotherapies, such as bortezomib treatment. However, resistance to bortezomib is frequently observed by mechanisms that remain to be deciphered. Bortezomib treatment leads to caspase activation and aggresome formation. Using models of patients-derived NB cell lines with different levels of sensitivity to bortezomib, we show that the activated form of caspase 3 accumulates within aggresomes of NB resistant cells leading to an impairment of bortezomib-induced apoptosis and increased cell survival. Our findings unveil a new mechanism of resistance to chemotherapy based on an altered subcellular distribution of the executioner caspase 3. This mechanism could explain the resistance developed in NB patients treated with bortezomib, emphasizing the potential of drugs targeting aggresomes.https://doi.org/10.1038/s41598-024-54140-7 |
| spellingShingle | Kévin Berthenet Eliézer Aïmontché Sara El Mrini Johan Brière Nathalie Pion Isabelle Iacono Stéphanie Brejon Karine Monier Frédéric Catez Gabriel Ichim Valérie Combaret Hichem C. Mertani Jean-Jacques Diaz Marie Alexandra Albaret Spatial sequestration of activated-caspase 3 in aggresomes mediates resistance of neuroblastoma cell to bortezomib treatment Scientific Reports |
| title | Spatial sequestration of activated-caspase 3 in aggresomes mediates resistance of neuroblastoma cell to bortezomib treatment |
| title_full | Spatial sequestration of activated-caspase 3 in aggresomes mediates resistance of neuroblastoma cell to bortezomib treatment |
| title_fullStr | Spatial sequestration of activated-caspase 3 in aggresomes mediates resistance of neuroblastoma cell to bortezomib treatment |
| title_full_unstemmed | Spatial sequestration of activated-caspase 3 in aggresomes mediates resistance of neuroblastoma cell to bortezomib treatment |
| title_short | Spatial sequestration of activated-caspase 3 in aggresomes mediates resistance of neuroblastoma cell to bortezomib treatment |
| title_sort | spatial sequestration of activated caspase 3 in aggresomes mediates resistance of neuroblastoma cell to bortezomib treatment |
| url | https://doi.org/10.1038/s41598-024-54140-7 |
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