Home > Publications database > Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors. > print

001     292537
005     20250818141006.0
024 7 _ |a 10.1016/j.xcrm.2024.101700
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100 1 _ |a Metselaar, Dennis S
|b 0
245 _ _ |a Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors.
260 _ _ |a Maryland Heights, MO
|c 2024
|b Elsevier
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500 _ _ |a 2024 Sep 17;5(9):101700
520 _ _ |a 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.
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650 _ 7 |a ATRT
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650 _ 7 |a atypical teratoid/rhabdoid tumor
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650 _ 7 |a gemcitabine
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650 _ 7 |a neuro oncology
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650 _ 7 |a p53
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650 _ 7 |a patient-derived models
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650 _ 7 |a pediatric oncology
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650 _ 7 |a sirtuin 1
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650 _ 7 |a therapy development
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700 1 _ |a Meel, Michaël H
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700 1 _ |a Goulding, Joshua R
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700 1 _ |a du Chatinier, Aimeé
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700 1 _ |a Rigamonti, Leyla
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700 1 _ |a Waranecki, Piotr
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700 1 _ |a Geisemeyer, Neal
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700 1 _ |a de Gooijer, Mark C
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700 1 _ |a Breur, Marjolein
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700 1 _ |a Koster, Jan
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700 1 _ |a Veldhuijzen van Zanten, Sophie E M
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700 1 _ |a Bugiani, Marianna
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700 1 _ |a Franke, Niels E
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700 1 _ |a Reddy, Alyssa
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700 1 _ |a Wesseling, Pieter
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700 1 _ |a Kaspers, Gertjan J L
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700 1 _ |a Hulleman, Esther
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773 _ _ |a 10.1016/j.xcrm.2024.101700
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