Enrichment of superoxide dismutase 2 in glioblastoma confers to acquisition of temozolomide resistance that is associated with tumor-initiating cell subsets.

Abstract

BACKGROUND:

Intratumor subsets with tumor-initiating features in glioblastoma are likely to survive treatment. Our goal is to identify the key factor in the process by which cells develop temozolomide (TMZ) resistance.

METHODS:

Resistant cell lines derived from U87MG and A172 were established through long-term co-incubation of TMZ. Primary tumors obtained from patients were maintained as patient-derived xenograft for studies of tumor-initating cell (TIC) features. The cell manifestations were assessed in the gene modulated cells for relevance to drug resistance.

RESULTS:

Among the mitochondria-related genes in the gene expression databases, superoxide dismutase 2 (SOD2) was a significant factor in resistance and patient survival. SOD2 in the resistant cells functionally determined the cell fate by limiting TMZ-stimulated superoxide reaction and cleavage of caspase-3. Genetic inhibition of the protein led to retrieval of drug effect in mouse study. SOD2 was also associated with the TIC features, which enriched in the resistant cells. The CD133+ specific subsets in the resistant cells exhibited superior superoxide regulation and the SOD2-related caspase-3 reaction. Experiments applying SOD2 modulation showed a positive correlation between the TIC features and the protein expression. Finally, co-treatment with TMZ and the SOD inhibitor sodium diethyldithiocarbamate trihydrate in xenograft mouse models with the TMZ-resistant primary tumor resulted in lower tumor proliferation, longer survival, and less CD133, Bmi-1, and SOD2 expression.

CONCLUSION:

SOD2 plays crucial roles in the tumor-initiating features that are related to TMZ resistance. Inhibition of the protein is a potential therapeutic strategy that can be used to enhance the effects of chemotherapy.

• Authors: Chia-Hung Chien, Jian-Ying Chuang, Shun-Tai Yang, Wen-Bin Yang, Pin-Yuan Chen, Tsung-I Hsu, Chih-Yuan Huang, Wei-Lun Lo, Ka-Yen Yang, Ming-Sheng Liu, Jui-Mei Chu, Pei-Hsuan Chung, Jr-Jiun Liu, Shao-Wen Chou, Shang-Hung Chen, Kwang-Yu Chang
• Journal: Journal of biomedical science (J Biomed Sci) Vol. 26 Issue 1 Pg. 77 (Oct 19 2019) ISSN: 1423-0127 [Electronic] England
• PMID: 31629402 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Alkylating
• Superoxide Dismutase
• superoxide dismutase 2
• Temozolomide

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioblastoma (drug therapy)
• Heterografts (physiopathology)
• Humans
• Mice
• Neoplastic Stem Cells (drug effects, physiology)
• Superoxide Dismutase (administration & dosage)
• Temozolomide (pharmacology)