| Autor: |
Dennis S. Metselaar, Michaël H. Meel, Joshua R. Goulding, Aimeé du Chatinier, Leyla Rigamonti, Piotr Waranecki, Neal Geisemeyer, Mark C. de Gooijer, Marjolein Breur, Jan Koster, Sophie E.M. Veldhuijzen van Zanten, Marianna Bugiani, Niels E. Franke, Alyssa Reddy, Pieter Wesseling, Gertjan J.L. Kaspers, Esther Hulleman |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Cell Reports Medicine, Vol 5, Iss 9, Pp 101700- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2666-3791 |
| DOI: |
10.1016/j.xcrm.2024.101700 |
| Popis: |
Summary: Atypical teratoid/rhabdoid tumors (ATRTs) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Using a newly developed and validated patient-derived ATRT culture and xenograft model, alongside a panel of primary ATRT models, we found that ATRTs are selectively sensitive to the nucleoside analog gemcitabine. Gene expression and protein analyses indicate that gemcitabine treatment causes the degradation of sirtuin 1 (SIRT1), resulting in cell death through activation of nuclear factor κB (NF-κB) and p53. Furthermore, we discovered that gemcitabine-induced loss of SIRT1 results in a nucleus-to-cytoplasm translocation of the sonic hedgehog (SHH) signaling activator GLI2, explaining the observed additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of ATRT xenograft-bearing mice with gemcitabine resulted in a >30% increase in median survival and yielded long-term survivors in two independent patient-derived xenograft models. These findings demonstrate that ATRTs are highly sensitive to gemcitabine treatment and may form part of a future multimodal treatment strategy for ATRTs. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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