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Autoren: Beltzig, Lea
Schwarzenbach, Christian
Leukel, Petra
Frauenknecht, Katrin B. M.
Sommer, Clemens
Tancredi, Alessandro
Hegi, Monika E.
Christmann, Markus
Kaina, Bernd
Titel: Senescence Is the main trait induced by temozolomide in glioblastoma cells
Online-Publikationsdatum: 20-Dez-2022
Erscheinungsdatum: 2022
Sprache des Dokuments: Englisch
Zusammenfassung/Abstract: First-line drug in the treatment of glioblastoma, the most severe brain cancer, is temozolomide (TMZ), a DNA-methylating agent that induces the critical damage O6-methylguanine (O6MeG). This lesion is cytotoxic through the generation of mismatch repair-mediated DNA double-strand breaks (DSBs), which trigger apoptotic pathways. Previously, we showed that O6MeG also induces cellular senescence (CSEN). Here, we show that TMZ-induced CSEN is a late response which has similar kinetics to apoptosis, but at a fourfold higher level. CSEN cells show a high amount of DSBs, which are located outside of telomeres, a high level of ROS and oxidized DNA damage (8-oxo-guanine), and sustained activation of the DNA damage response and histone methylation. Despite the presence of DSBs, CSEN cells are capable of repairing radiation-induced DSBs. Glioblastoma cells that acquired resistance to TMZ became simultaneously resistant to TMZ-induced CSEN. Using a Tet-On glioblastoma cell system, we show that upregulation of MGMT immediately after TMZ completely abrogated apoptosis and CSEN, while induction of MGMT long-term (>72 h) after TMZ did not reduce apoptosis and CSEN. Furthermore, upregulation of MGMT in the senescent cell population had no impact on the survival of senescent cells, indicating that O6MeG is required for induction, but not for maintenance of the senescent state. We further show that, in recurrent GBM specimens, a significantly higher level of DSBs and CSEN-associated histone H3K27me3 was observed than in the corresponding primary tumors. Overall, the data indicate that CSEN is a key node induced in GBM following chemotherapy.
DDC-Sachgruppe: 610 Medizin
610 Medical sciences
Veröffentlichende Institution: Johannes Gutenberg-Universität Mainz
Organisationseinheit: FB 04 Medizin
Veröffentlichungsort: Mainz
ROR: https://ror.org/023b0x485
DOI: http://doi.org/10.25358/openscience-7245
Version: Published version
Publikationstyp: Zeitschriftenaufsatz
Weitere Angaben zur Dokumentart: Scientific article
Nutzungsrechte: CC BY
Informationen zu den Nutzungsrechten: https://creativecommons.org/licenses/by/4.0/
Zeitschrift: Cancers
14
9
Seitenzahl oder Artikelnummer: 2233
Verlag: MDPI
Verlagsort: Basel
Erscheinungsdatum: 2022
ISSN: 2072-6694
URL der Originalveröffentlichung: https://doi.org/10.3390/cancers14092233
DOI der Originalveröffentlichung: 10.3390/cancers14092233
Enthalten in den Sammlungen:DFG-491381577-G

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