The Sec61 translocon is a therapeutic vulnerability in multiple myeloma
Abstract Multiple myeloma (MM) is an incurable malignancy characterized by the uncontrolled expansion of plasma cells in the bone marrow. While proteasome inhibitors like bortezomib efficiently halt MM progression, drug resistance inevitably develop, and novel therapeutic approaches are needed. Here...
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-01-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114740 |
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| author | Antoine Domenger Caroline Choisy Ludivine Baron Véronique Mayau Emeline Perthame Ludovic Deriano Bertrand Arnulf Jean‐Christophe Bories Gilles Dadaglio Caroline Demangel |
| author_facet | Antoine Domenger Caroline Choisy Ludivine Baron Véronique Mayau Emeline Perthame Ludovic Deriano Bertrand Arnulf Jean‐Christophe Bories Gilles Dadaglio Caroline Demangel |
| author_sort | Antoine Domenger |
| collection | DOAJ |
| description | Abstract Multiple myeloma (MM) is an incurable malignancy characterized by the uncontrolled expansion of plasma cells in the bone marrow. While proteasome inhibitors like bortezomib efficiently halt MM progression, drug resistance inevitably develop, and novel therapeutic approaches are needed. Here, we used a recently discovered Sec61 inhibitor, mycolactone, to assess the interest of disrupting MM proteostasis via protein translocation blockade. In human MM cell lines, mycolactone caused rapid defects in secretion of immunoglobulins and expression of pro‐survival interleukin (IL)‐6 receptor and CD40, whose activation stimulates IL‐6 production. Mycolactone also triggered pro‐apoptotic endoplasmic reticulum stress responses synergizing with bortezomib for induction of MM cell death and overriding acquired resistance to the proteasome inhibitor. Notably, the mycolactone–bortezomib combination rapidly killed patient‐derived MM cells ex vivo, but not normal mononuclear cells. In immunodeficient mice engrafted with MM cells, it demonstrated superior therapeutic efficacy over single drug treatments, without inducing toxic side effects. Collectively, these findings establish Sec61 blockers as novel anti‐MM agents and reveal the interest of targeting both the translocon and the proteasome in proteostasis‐addicted tumors. |
| format | Article |
| id | doaj-art-22da9be175514a33a0ab22c7d255aaf8 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-22da9be175514a33a0ab22c7d255aaf82025-08-20T04:03:07ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-01-0114311710.15252/emmm.202114740The Sec61 translocon is a therapeutic vulnerability in multiple myelomaAntoine Domenger0Caroline Choisy1Ludivine Baron2Véronique Mayau3Emeline Perthame4Ludovic Deriano5Bertrand Arnulf6Jean‐Christophe Bories7Gilles Dadaglio8Caroline Demangel9Unité d’Immunobiologie de l’Infection, Institut Pasteur, INSERM U1224, Université de ParisINSERM U976, Institut de Recherche Saint Louis, Université de ParisUnité d’Immunobiologie de l’Infection, Institut Pasteur, INSERM U1224, Université de ParisUnité d’Immunobiologie de l’Infection, Institut Pasteur, INSERM U1224, Université de ParisBioinformatics and Biostatistics Hub, Institut Pasteur, Université de ParisUnité d’Intégrité du Génome, Immunité et Cancer, Equipe Labellisée Ligue Contre Le Cancer, Institut Pasteur, INSERM U1223, Université de ParisINSERM U976, Institut de Recherche Saint Louis, Université de ParisINSERM U976, Institut de Recherche Saint Louis, Université de ParisUnité d’Immunobiologie de l’Infection, Institut Pasteur, INSERM U1224, Université de ParisUnité d’Immunobiologie de l’Infection, Institut Pasteur, INSERM U1224, Université de ParisAbstract Multiple myeloma (MM) is an incurable malignancy characterized by the uncontrolled expansion of plasma cells in the bone marrow. While proteasome inhibitors like bortezomib efficiently halt MM progression, drug resistance inevitably develop, and novel therapeutic approaches are needed. Here, we used a recently discovered Sec61 inhibitor, mycolactone, to assess the interest of disrupting MM proteostasis via protein translocation blockade. In human MM cell lines, mycolactone caused rapid defects in secretion of immunoglobulins and expression of pro‐survival interleukin (IL)‐6 receptor and CD40, whose activation stimulates IL‐6 production. Mycolactone also triggered pro‐apoptotic endoplasmic reticulum stress responses synergizing with bortezomib for induction of MM cell death and overriding acquired resistance to the proteasome inhibitor. Notably, the mycolactone–bortezomib combination rapidly killed patient‐derived MM cells ex vivo, but not normal mononuclear cells. In immunodeficient mice engrafted with MM cells, it demonstrated superior therapeutic efficacy over single drug treatments, without inducing toxic side effects. Collectively, these findings establish Sec61 blockers as novel anti‐MM agents and reveal the interest of targeting both the translocon and the proteasome in proteostasis‐addicted tumors.https://doi.org/10.15252/emmm.202114740multiple myelomaproteostatic stressSec61 translocon |
| spellingShingle | Antoine Domenger Caroline Choisy Ludivine Baron Véronique Mayau Emeline Perthame Ludovic Deriano Bertrand Arnulf Jean‐Christophe Bories Gilles Dadaglio Caroline Demangel The Sec61 translocon is a therapeutic vulnerability in multiple myeloma EMBO Molecular Medicine multiple myeloma proteostatic stress Sec61 translocon |
| title | The Sec61 translocon is a therapeutic vulnerability in multiple myeloma |
| title_full | The Sec61 translocon is a therapeutic vulnerability in multiple myeloma |
| title_fullStr | The Sec61 translocon is a therapeutic vulnerability in multiple myeloma |
| title_full_unstemmed | The Sec61 translocon is a therapeutic vulnerability in multiple myeloma |
| title_short | The Sec61 translocon is a therapeutic vulnerability in multiple myeloma |
| title_sort | sec61 translocon is a therapeutic vulnerability in multiple myeloma |
| topic | multiple myeloma proteostatic stress Sec61 translocon |
| url | https://doi.org/10.15252/emmm.202114740 |
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