Gutenberg Open Science: Senescence Is the main trait induced by temozolomide in glioblastoma cells

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-7245

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DC Field	Value	Language
dc.contributor.author	Beltzig, Lea	-
dc.contributor.author	Schwarzenbach, Christian	-
dc.contributor.author	Leukel, Petra	-
dc.contributor.author	Frauenknecht, Katrin B. M.	-
dc.contributor.author	Sommer, Clemens	-
dc.contributor.author	Tancredi, Alessandro	-
dc.contributor.author	Hegi, Monika E.	-
dc.contributor.author	Christmann, Markus	-
dc.contributor.author	Kaina, Bernd	-
dc.date.accessioned	2022-12-20T12:12:24Z	-
dc.date.available	2022-12-20T12:12:24Z	-
dc.date.issued	2022	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/7259	-
dc.description.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.	en_GB
dc.description.sponsorship	Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577	de
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	Senescence Is the main trait induced by temozolomide in glioblastoma cells	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-7245	-
jgu.type.contenttype	Scientific article	de
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 04 Medizin	de
jgu.organisation.number	2700	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Cancers	de
jgu.journal.volume	14	de
jgu.journal.issue	9	de
jgu.pages.alternative	2233	de
jgu.publisher.year	2022	-
jgu.publisher.name	MDPI	de
jgu.publisher.place	Basel	de
jgu.publisher.uri	https://doi.org/10.3390/cancers14092233	de
jgu.publisher.issn	2072-6694	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	610	de
jgu.publisher.doi	10.3390/cancers14092233	de
jgu.organisation.ror	https://ror.org/023b0x485	-
jgu.subject.dfg	Naturwissenschaften	de
Appears in collections:	DFG-491381577-G

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