Senescence Is the Main Trait Induced by Temozolomide in Glioblastoma Cells.

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Version: author
License: CC BY 4.0
Serval ID
serval:BIB_2FB34E2C0D95
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Senescence Is the Main Trait Induced by Temozolomide in Glioblastoma Cells.
Journal
Cancers
Author(s)
Beltzig L., Schwarzenbach C., Leukel P., Frauenknecht KBM, Sommer C., Tancredi A., Hegi M.E., Christmann M., Kaina B.
ISSN
2072-6694 (Print)
ISSN-L
2072-6694
Publication state
Published
Issued date
29/04/2022
Peer-reviewed
Oui
Volume
14
Number
9
Pages
2233
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
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 O <sup>6</sup> -methylguanine (O <sup>6</sup> MeG). This lesion is cytotoxic through the generation of mismatch repair-mediated DNA double-strand breaks (DSBs), which trigger apoptotic pathways. Previously, we showed that O <sup>6</sup> MeG 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 (&gt;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 O <sup>6</sup> MeG 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.
Keywords
MGMT, O6-methylguanine, apoptosis, glioblastoma, senescence, temozolomide
Pubmed
Web of science
Open Access
Yes
Funding(s)
Swiss National Science Foundation / Projects
Create date
23/05/2022 13:07
Last modification date
08/06/2022 6:08
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