Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase

Kwang Yu Chang, Tsung I. Hsu, Che Chia Hsu, Shan Yin Tsai, Jr Jiun Liu, Shao Wen Chou, Ming Sheng Liu, Jing Ping Liou, Chiung Yuan Ko, Kai Yun Chen, Jan Jong Hung, Wen Chang Chang, Cheng Keng Chuang, Tzu Jen Kao, Jian Ying Chuang

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Acquisition of temozolomide (TMZ) resistance is a major factor leading to the failure of glioblastoma (GBM) treatment. The exact mechanism by which GBM evades TMZ toxicity is not always related to the expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), and so remains unclear. In this study, TMZ-resistant variants derived from MGMT-negative GBM clinical samples and cell lines were studied, revealing there to be increased specificity protein 1 (Sp1) expression associated with reduced reactive oxygen species (ROS) accumulation following TMZ treatment. Analysis of gene expression databases along with cell studies identified the ROS scavenger superoxide dismutase 2 (SOD2) as being disease-related. SOD2 expression was also increased, and it was found to be co-expressed with Sp1 in TMZ-resistant cells. Investigation of the SOD2 promoter revealed Sp1 as a critical transcriptional activator that enhances SOD2 gene expression. Co-treatment with an Sp1 inhibitor restored the inhibitory effects of TMZ, and decreased SOD2 levels in TMZ-resistant cells. This treatment strategy restored susceptibility to TMZ in xenograft animals, leading to prolonged survival in an orthotopic model. Thus, our results suggest that Sp1 modulates ROS scavengers as a novel mechanism to increase cancer malignancy and resistance to chemotherapy. Inhibition of this pathway may represent a potential therapeutic target for restoring treatment susceptibility in GBM.

Original languageEnglish
Pages (from-to)655-664
Number of pages10
JournalRedox Biology
Volume13
DOIs
Publication statusPublished - 2017 Oct

All Science Journal Classification (ASJC) codes

  • Organic Chemistry
  • Clinical Biochemistry

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