Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors.

Autor:	Metselaar DS; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands., Meel MH; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands., Goulding JR; Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands., du Chatinier A; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Rigamonti L; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Waranecki P; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands., Geisemeyer N; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany., de Gooijer MC; Division of Pharmacology/Mouse Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Breur M; Department of Pathology, Amsterdam University Medical Centers, Amsterdam, the Netherlands., Koster J; Department of Epidemiology and Biostatistics, Amsterdam University Medical Centers, Amsterdam, the Netherlands., Veldhuijzen van Zanten SEM; Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands., Bugiani M; Department of Pathology, Amsterdam University Medical Centers, Amsterdam, the Netherlands., Franke NE; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Reddy A; Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, CA, USA., Wesseling P; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Pathology, Amsterdam University Medical Centers, Amsterdam, the Netherlands., Kaspers GJL; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands., Hulleman E; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Departments of Pediatric Oncology/Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands. Electronic address: e.hulleman@prinsesmaximacentrum.nl.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Sep 17; Vol. 5 (9), pp. 101700. Date of Electronic Publication: 2024 Aug 28.
DOI:	10.1016/j.xcrm.2024.101700
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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