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
Affiliations
Kwang-Yu Chang
National Institute of Cancer Research, National Health Research Institutes, Taiwan
Tsung-I. Hsu
Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taiwan
Che-Chia Hsu
Graduate Institute of Medical Science, Taipei Medical University, Taiwan
Shan-Yin Tsai
An Nan Hospital, China Medical University, Taiwan
Jr-Jiun Liu
National Institute of Cancer Research, National Health Research Institutes, Taiwan
Shao-Wen Chou
National Institute of Cancer Research, National Health Research Institutes, Taiwan
Ming-Sheng Liu
National Institute of Cancer Research, National Health Research Institutes, Taiwan
Jing-Ping Liou
School of Pharmacy, Taipei Medical University, Taiwan
Chiung-Yuan Ko
The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taiwan
Kai-Yun Chen
The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taiwan
Jan-Jong Hung
Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Taiwan
Wen-Chang Chang
Graduate Institute of Medical Science, Taipei Medical University, Taiwan
Cheng-Keng Chuang
Department of Medicine, Chang Gung University, Taiwan
Tzu-Jen Kao
Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taiwan
Jian-Ying Chuang
Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taiwan
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.
