Reduced DDB2 Expression Is Associated with Temozolomide Resistance in Glioblastoma Cells
- 1Department of Genetics, University of Córdoba, 14014 Córdoba, Spain
- 2Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain
Abstract
Glioblastoma (GBM) remains one of the most lethal primary brain tumours, and resistance to temozolomide (TMZ), the standard chemotherapeutic agent for GBM, represents a major obstacle to effective treatment. Although O6-methylguanine-DNA methyltransferase (MGMT) is a well-established determinant of TMZ response, MGMT status alone does not fully explain the heterogeneity of treatment outcomes, suggesting the involvement of additional DNA damage response mechanisms. Here, we investigated the contribution of different DNA repair pathways to TMZ sensitivity in a panel of GBM cell lines displaying distinct TMZ response profiles. Expression analysis of 84 DNA repair genes identified damage-specific DNA binding protein 2 (DDB2) as the only one consistently associated with TMZ sensitivity. We found that DDB2 expression was significantly reduced in TMZ-resistant cell lines and selectively induced following TMZ exposure in TMZ-sensitive cells. Proteomic profiling of representative sensitive and resistant cell models further revealed distinct responses to TMZ and identified enrichment of p53-associated DNA damage response pathways in sensitive cells, including altered expression of DDB2 and other canonical p53-regulated proteins. Importantly, siRNA-mediated depletion of DDB2 in the TMZ-sensitive A172 GBM cell line significantly reduced TMZ sensitivity. These findings provide functional evidence that DDB2 contributes to the cellular response to TMZ and extend the established roles of DDB2 in DNA repair and cancer biology to TMZ responsiveness in GBM.
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BibTeX
@article{gravaloscano2026reduced,
title = {{Reduced DDB2 Expression Is Associated with Temozolomide Resistance in Glioblastoma Cells}},
author = {Inés Grávalos-Cano and Teresa Morales-Ruiz and Rafael R. Ariza and Teresa Roldán-Arjona and María Isabel Martínez-Macías},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27208941},
url = {https://www.mdpi.com/1422-0067/27/20/8941},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Reduced DDB2 Expression Is Associated with Temozolomide Resistance in Glioblastoma Cells
AU - Inés Grávalos-Cano
AU - Teresa Morales-Ruiz
AU - Rafael R. Ariza
AU - Teresa Roldán-Arjona
AU - María Isabel Martínez-Macías
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27208941
UR - https://www.mdpi.com/1422-0067/27/20/8941
AB - Glioblastoma (GBM) remains one of the most lethal primary brain tumours, and resistance to temozolomide (TMZ), the standard chemotherapeutic agent for GBM, represents a major obstacle to effective treatment. Although O6-methylguanine-DNA methyltransferase (MGMT) is a well-established determinant of TMZ response, MGMT status alone does not fully explain the heterogeneity of treatment outcomes, suggesting the involvement of additional DNA damage response mechanisms. Here, we investigated the contribution of different DNA repair pathways to TMZ sensitivity in a panel of GBM cell lines displaying distinct TMZ response profiles. Expression analysis of 84 DNA repair genes identified damage-specific DNA binding protein 2 (DDB2) as the only one consistently associated with TMZ sensitivity. We found that DDB2 expression was significantly reduced in TMZ-resistant cell lines and selectively induced following TMZ exposure in TMZ-sensitive cells. Proteomic profiling of representative sensitive and resistant cell models further revealed distinct responses to TMZ and identified enrichment of p53-associated DNA damage response pathways in sensitive cells, including altered expression of DDB2 and other canonical p53-regulated proteins. Importantly, siRNA-mediated depletion of DDB2 in the TMZ-sensitive A172 GBM cell line significantly reduced TMZ sensitivity. These findings provide functional evidence that DDB2 contributes to the cellular response to TMZ and extend the established roles of DDB2 in DNA repair and cancer biology to TMZ responsiveness in GBM.
SN - 1422-0067
ER -