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Enrichment of Superoxide Dismutase 2 in Glioblastoma Confers to Acquisition of Temozolomide Resistance That Is Associated With Tumor-Initiating Cell Subsets

Enrichment of Superoxide Dismutase 2 in Glioblastoma Confers to Acquisition of Temozolomide Resistance That Is Associated With Tumor-Initiating Cell Subsets

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, etc.

J Biomed Sci. 2019 Oct 19;26(1):77.

PMID: 31629402

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP20624253	Sodium diethyldithiocarbamate trihydrate		20624-25-3	Price

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