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BRAT1 - a new therapeutic target for glioblastoma.

Authors :
Haydo, Alicia
Schmidt, Jennifer
Crider, Alisha
Kögler, Tim
Ertl, Johanna
Hehlgans, Stephanie
Hoffmann, Marina E.
Rathore, Rajeshwari
Güllülü, Ömer
Wang, Yecheng
Zhang, Xiangke
Herold-Mende, Christel
Pampaloni, Francesco
Tegeder, Irmgard
Dikic, Ivan
Dai, Mingji
Rödel, Franz
Kögel, Donat
Linder, Benedikt
Source :
Cellular & Molecular Life Sciences; 1/21/2025, Vol. 82 Issue 1, p1-23, 23p
Publication Year :
2025

Abstract

Glioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of BRCA1-associated ATM activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated by in vitro and in vivo studies demonstrating impaired tumor growth and invasion. Proteomic and phosphoproteomic analyses further emphasize the role of BRAT1's cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in an ex vivo slice culture model, particularly when combined with irradiation, resulting in a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
1420682X
Volume :
82
Issue :
1
Database :
Complementary Index
Journal :
Cellular & Molecular Life Sciences
Publication Type :
Academic Journal
Accession number :
182323494
Full Text :
https://doi.org/10.1007/s00018-024-05553-0