Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress
Abstract Chemotherapy still constitutes the standard of care for the treatment of most neoplastic diseases. Certain chemotherapeutics from the oncological armamentarium are able to trigger pre‐mortem stress signals that lead to immunogenic cell death (ICD), thus inducing an antitumor immune response...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911622 |
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| author | Juliette Humeau Allan Sauvat Giulia Cerrato Wei Xie Friedemann Loos Francesca Iannantuoni Lucillia Bezu Sarah Lévesque Juliette Paillet Jonathan Pol Marion Leduc Laurence Zitvogel Hugues de Thé Oliver Kepp Guido Kroemer |
| author_facet | Juliette Humeau Allan Sauvat Giulia Cerrato Wei Xie Friedemann Loos Francesca Iannantuoni Lucillia Bezu Sarah Lévesque Juliette Paillet Jonathan Pol Marion Leduc Laurence Zitvogel Hugues de Thé Oliver Kepp Guido Kroemer |
| author_sort | Juliette Humeau |
| collection | DOAJ |
| description | Abstract Chemotherapy still constitutes the standard of care for the treatment of most neoplastic diseases. Certain chemotherapeutics from the oncological armamentarium are able to trigger pre‐mortem stress signals that lead to immunogenic cell death (ICD), thus inducing an antitumor immune response and mediating long‐term tumor growth reduction. Here, we used an established model, built on artificial intelligence to identify, among a library of 50,000 compounds, anticancer agents that, based on their molecular descriptors, were predicted to induce ICD. This algorithm led us to the identification of dactinomycin (DACT, best known as actinomycin D), a highly potent cytotoxicant and ICD inducer that mediates immune‐dependent anticancer effects in vivo. Since DACT is commonly used as an inhibitor of DNA to RNA transcription, we investigated whether other experimentally established or algorithm‐selected, clinically employed ICD inducers would share this characteristic. As a common leitmotif, a panel of pharmacological ICD stimulators inhibited transcription and secondarily translation. These results establish the inhibition of RNA synthesis as an initial event for ICD induction. |
| format | Article |
| id | doaj-art-9ac05f98dda3489daa122aa6f33d4ae1 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-9ac05f98dda3489daa122aa6f33d4ae12025-08-20T04:03:01ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-04-0112512210.15252/emmm.201911622Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stressJuliette Humeau0Allan Sauvat1Giulia Cerrato2Wei Xie3Friedemann Loos4Francesca Iannantuoni5Lucillia Bezu6Sarah Lévesque7Juliette Paillet8Jonathan Pol9Marion Leduc10Laurence Zitvogel11Hugues de Thé12Oliver Kepp13Guido Kroemer14Equipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisFaculty of Medicine Kremlin Bicêtre, Université Paris Sud, Paris SaclayCollege de France, INSERM UMR 1050, CNRS UMR 7241, PSL UniversityEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisEquipe ItemNumberlisée par la Ligue contre le Cancer, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Université de ParisAbstract Chemotherapy still constitutes the standard of care for the treatment of most neoplastic diseases. Certain chemotherapeutics from the oncological armamentarium are able to trigger pre‐mortem stress signals that lead to immunogenic cell death (ICD), thus inducing an antitumor immune response and mediating long‐term tumor growth reduction. Here, we used an established model, built on artificial intelligence to identify, among a library of 50,000 compounds, anticancer agents that, based on their molecular descriptors, were predicted to induce ICD. This algorithm led us to the identification of dactinomycin (DACT, best known as actinomycin D), a highly potent cytotoxicant and ICD inducer that mediates immune‐dependent anticancer effects in vivo. Since DACT is commonly used as an inhibitor of DNA to RNA transcription, we investigated whether other experimentally established or algorithm‐selected, clinically employed ICD inducers would share this characteristic. As a common leitmotif, a panel of pharmacological ICD stimulators inhibited transcription and secondarily translation. These results establish the inhibition of RNA synthesis as an initial event for ICD induction.https://doi.org/10.15252/emmm.201911622dactinomycineIF2α phosphorylationimmunogenic cell deathtranscriptiontranslation |
| spellingShingle | Juliette Humeau Allan Sauvat Giulia Cerrato Wei Xie Friedemann Loos Francesca Iannantuoni Lucillia Bezu Sarah Lévesque Juliette Paillet Jonathan Pol Marion Leduc Laurence Zitvogel Hugues de Thé Oliver Kepp Guido Kroemer Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress EMBO Molecular Medicine dactinomycin eIF2α phosphorylation immunogenic cell death transcription translation |
| title | Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress |
| title_full | Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress |
| title_fullStr | Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress |
| title_full_unstemmed | Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress |
| title_short | Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress |
| title_sort | inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress |
| topic | dactinomycin eIF2α phosphorylation immunogenic cell death transcription translation |
| url | https://doi.org/10.15252/emmm.201911622 |
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