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NEIL1 suppresses ROS accumulation to promote temozolomide resistance and malignant progression in glioma cells
Shuo Li1, Chenhao Fang2, Qingyue Yuan1
1Department of Neurosurgery, Shanghai Tenth People's Hospital, Clinical Medical College of Nanjing Medical University, Nanjing 211166, China; Department of Neurosurgery, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Background:
Glioma is the most common malignant primary brain tumor. Temozolomide (TMZ) is the standard first-line chemotherapy, but its efficacy is severely limited by acquired resistance. Understanding resistance mechanisms, especially beyond traditional DNA repair, is crucial for improving outcomes.
Methods:
We integrated multi-database glioma transcriptomics (TCGA, GTEx, CGGA). Bioinformatics (differential expression, WGCNA, glycolipid metabolism gene screening) and machine learning (LASSO, random forest) identified key genes, focusing on the DNA glycosylase NEIL1. Its expression was assessed in U251 MG cells versus TMZ-resistant (U251 MG/TMZ) cells. Gain/loss-of-function studies (lentiviral knockdown/overexpression) and pharmacological inhibition (a 2-thioxanthine derivative, TX16) were used to evaluate NEIL1's role in proliferation (CCK-8, EdU), migration, invasion, apoptosis (TUNEL), ROS, and TMZ sensitivity (IC50). A subcutaneous nude mouse model provided in vivo validation.
Results:
NEIL1 was aberrantly expressed in glioma and enriched in PI3K-Akt/cAMP signaling, suggesting that it may promote the malignant behavior of U251 MG cells through these pathways. Its expression was significantly higher in TMZ-resistant cells (P < 0.001). NEIL1 overexpression promoted malignant phenotypes (proliferation, migration, invasion, P < 0.05), while its knockdown suppressed them. Critically, NEIL1 overexpression attenuated TMZ-induced ROS and DNA damage, increased cell viability and IC50 (1.2-fold), and bolstered TMZ resistance. The NEIL1 inhibitor TX16 reversed these malignant behaviors and restored TMZ sensitivity (P < 0.05), reinstating ROS-driven apoptosis. In vivo, NEIL1 promoted tumor growth, which was suppressed by TX16.
Conclusion:
NEIL1 drives glioma malignancy and TMZ resistance by mitigating oxidative stress and DNA damage, highlighting its role as a promising target to overcome chemoresistance.
Insights
The DNA glycosylase NEIL1 promotes glioma malignancy and temozolomide (TMZ) resistance by reducing oxidative stress and DNA damage. Inhibiting NEIL1 with TX16 restores TMZ sensitivity, offering a potential strategy to overcome chemoresistance.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Glioma is the most common primary brain malignancy.
- Temozolomide (TMZ) resistance limits treatment efficacy.
- Understanding novel resistance mechanisms is critical.
Purpose of the Study:
- Identify key genes involved in glioma malignancy and TMZ resistance.
- Investigate the role of DNA glycosylase NEIL1 in glioma.
- Evaluate NEIL1 as a therapeutic target for overcoming TMZ resistance.
Main Methods:
- Integrated multi-database glioma transcriptomics (TCGA, GTEx, CGGA).
- Applied bioinformatics and machine learning to identify key genes, focusing on NEIL1.
- Utilized in vitro (cell lines) and in vivo (mouse models) experiments, including gain/loss-of-function studies and pharmacological inhibition.
Main Results:
- NEIL1 expression is elevated in glioma and significantly higher in TMZ-resistant cells.
- NEIL1 overexpression promotes glioma cell proliferation, migration, and invasion.
- NEIL1 confers TMZ resistance by attenuating oxidative stress and DNA damage, while its inhibition restores sensitivity.
Conclusions:
- NEIL1 drives glioma malignancy and temozolomide resistance.
- NEIL1 mitigates oxidative stress and DNA damage, contributing to chemoresistance.
- Targeting NEIL1 represents a promising strategy to enhance glioma treatment outcomes.
