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, Shang Hung Chen, Kwang Yu Chang

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Article number77
JournalJournal of Biomedical Science
Volume26
Issue number1
DOIs
Publication statusPublished - Oct 19 2019

Keywords

  • Glioblastoma
  • ROS
  • SOD2
  • Temozolomide
  • Tumor-initiating cells

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Pharmacology (medical)

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