Identification of a small molecule targeting EPLIN as a novel strategy for the treatment of pediatric neuroblastoma and medulloblastoma
Abstract Amplification of the MYCN proto-oncogene serves as a key marker of aggressive disease and poor treatment outcomes in certain pediatric tumors originating from the nervous system, including neuroblastoma and medulloblastoma. However, the complex nature of the challenging MYCN protein undersc...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07876-7 |
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| author | Emma Lindell Jing Guo Miao Zhao Natallia Rameika Xi Lu Tabea Wacker Lei Zhong Tobias Bergström Sara Svanberg Azazul I. Chowdhury Peter Bergsten Xingqi Chen Daniel Bexell Fredrik J. Swartling Tobias Sjöblom Xiaonan Zhang |
| author_facet | Emma Lindell Jing Guo Miao Zhao Natallia Rameika Xi Lu Tabea Wacker Lei Zhong Tobias Bergström Sara Svanberg Azazul I. Chowdhury Peter Bergsten Xingqi Chen Daniel Bexell Fredrik J. Swartling Tobias Sjöblom Xiaonan Zhang |
| author_sort | Emma Lindell |
| collection | DOAJ |
| description | Abstract Amplification of the MYCN proto-oncogene serves as a key marker of aggressive disease and poor treatment outcomes in certain pediatric tumors originating from the nervous system, including neuroblastoma and medulloblastoma. However, the complex nature of the challenging MYCN protein underscores the urgent need for additional targets and therapies to tackle neuroblastoma and medulloblastoma. In this study, with a primary focus on neuroblastoma and the aim of also benefiting children with medulloblastoma, we identified FLIX5, a small compound that exhibits broad cytotoxicity against both neuroblastoma and medulloblastoma cells, primarily by triggering apoptosis. Furthermore, FLIX5 enhances the cholesterol dependency of neuroblastoma cells under conditions where mitochondrial function is impaired. FLIX5 as well shows a synergistic effect when combined with vincristine, a conventional anticancer drug, against neuroblastoma cells and organoids. Through proteome integral solubility alteration, computational molecular docking predictions, and cellular thermal shift assays for target identification and validation, FLIX5 reveals EPLIN (Epithelial Protein Lost In Neoplasm) as a previously unexplored drug target. EPLIN is involved in several cellular processes, including cholesterol uptake and mitochondrial function. The discovery of FLIX5 targeting EPLIN presents new opportunities for treating malignant pediatric tumors, with the potential to target chemoresistant dormant cancer cells and broaden its therapeutic applications to other tumor types. |
| format | Article |
| id | doaj-art-567c6c3fbde5471ebd08c0425c566a79 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-567c6c3fbde5471ebd08c0425c566a792025-08-20T03:46:20ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111510.1038/s41419-025-07876-7Identification of a small molecule targeting EPLIN as a novel strategy for the treatment of pediatric neuroblastoma and medulloblastomaEmma Lindell0Jing Guo1Miao Zhao2Natallia Rameika3Xi Lu4Tabea Wacker5Lei Zhong6Tobias Bergström7Sara Svanberg8Azazul I. Chowdhury9Peter Bergsten10Xingqi Chen11Daniel Bexell12Fredrik J. Swartling13Tobias Sjöblom14Xiaonan Zhang15Department of Immunology, Genetics and Pathology, Uppsala UniversityCentre for Computational Biology, Duke-NUS Medical SchoolDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Medical Cell Biology, Uppsala University, BMC, Husargatan 3Department of Medical Cell Biology, Uppsala University, BMC, Husargatan 3Department of Immunology, Genetics and Pathology, Uppsala UniversityDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityAbstract Amplification of the MYCN proto-oncogene serves as a key marker of aggressive disease and poor treatment outcomes in certain pediatric tumors originating from the nervous system, including neuroblastoma and medulloblastoma. However, the complex nature of the challenging MYCN protein underscores the urgent need for additional targets and therapies to tackle neuroblastoma and medulloblastoma. In this study, with a primary focus on neuroblastoma and the aim of also benefiting children with medulloblastoma, we identified FLIX5, a small compound that exhibits broad cytotoxicity against both neuroblastoma and medulloblastoma cells, primarily by triggering apoptosis. Furthermore, FLIX5 enhances the cholesterol dependency of neuroblastoma cells under conditions where mitochondrial function is impaired. FLIX5 as well shows a synergistic effect when combined with vincristine, a conventional anticancer drug, against neuroblastoma cells and organoids. Through proteome integral solubility alteration, computational molecular docking predictions, and cellular thermal shift assays for target identification and validation, FLIX5 reveals EPLIN (Epithelial Protein Lost In Neoplasm) as a previously unexplored drug target. EPLIN is involved in several cellular processes, including cholesterol uptake and mitochondrial function. The discovery of FLIX5 targeting EPLIN presents new opportunities for treating malignant pediatric tumors, with the potential to target chemoresistant dormant cancer cells and broaden its therapeutic applications to other tumor types.https://doi.org/10.1038/s41419-025-07876-7 |
| spellingShingle | Emma Lindell Jing Guo Miao Zhao Natallia Rameika Xi Lu Tabea Wacker Lei Zhong Tobias Bergström Sara Svanberg Azazul I. Chowdhury Peter Bergsten Xingqi Chen Daniel Bexell Fredrik J. Swartling Tobias Sjöblom Xiaonan Zhang Identification of a small molecule targeting EPLIN as a novel strategy for the treatment of pediatric neuroblastoma and medulloblastoma Cell Death and Disease |
| title | Identification of a small molecule targeting EPLIN as a novel strategy for the treatment of pediatric neuroblastoma and medulloblastoma |
| title_full | Identification of a small molecule targeting EPLIN as a novel strategy for the treatment of pediatric neuroblastoma and medulloblastoma |
| title_fullStr | Identification of a small molecule targeting EPLIN as a novel strategy for the treatment of pediatric neuroblastoma and medulloblastoma |
| title_full_unstemmed | Identification of a small molecule targeting EPLIN as a novel strategy for the treatment of pediatric neuroblastoma and medulloblastoma |
| title_short | Identification of a small molecule targeting EPLIN as a novel strategy for the treatment of pediatric neuroblastoma and medulloblastoma |
| title_sort | identification of a small molecule targeting eplin as a novel strategy for the treatment of pediatric neuroblastoma and medulloblastoma |
| url | https://doi.org/10.1038/s41419-025-07876-7 |
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