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

被引：60

作者：

Chang, Kwang-Yu ^{[1
,2
]}

Hsu, Tsung-I. ^{[3
]}

Hsu, Che-Chia ^{[4
,5
]}

Tsai, Shan-Yin ^{[6
]}

Liu, Jr-Jiun ^{[1
,7
]}

Chou, Shao-Wen ^{[1
]}

Liu, Ming-Sheng ^{[1
]}

Liou, Jing-Ping ^{[8
]}

Ko, Chiung-Yuan ^{[7
]}

Chen, Kai-Yun ^{[7
]}

Hung, Jan-Jong ^{[9
]}

Chang, Wen-Chang ^{[4
]}

Chuang, Cheng-Keng ^{[10
,11
]}

Kao, Tzu-Jen ^{[3
,7
]}

Chuang, Jian-Ying ^{[3
,7
]}

机构：

[1] Natl Hlth Res Inst, Natl Inst Canc Res, Zhunan Township, Miaoli County, Taiwan

[2] Natl Cheng Kung Univ Hosp, Dept Internal Med, Tainan, Taiwan

[3] Taipei Med Univ, Ctr Neurotrauma & Neuroregenerat, Taipei, Taiwan

[4] Taipei Med Univ, Grad Inst Med Sci, Taipei, Taiwan

[5] Wake Forest Sch Med, Dept Canc Biol, Winston Salem, NC USA

[6] China Med Univ, An Nan Hosp, Taichung, Taiwan

[7] Taipei Med Univ, PhD Program Neural Regenerat Med, 250 Wuxing St, Taipei 110, Taiwan

[8] Taipei Med Univ, Sch Pharm, Taipei, Taiwan

[9] Natl Cheng Kung Univ, Inst Bioinformat & Biosignal Transduct, Tainan, Taiwan

[10] Chang Gung Univ, Dept Med, Taoyuan, Taiwan

[11] Linkou Chang Gung Mem Hosp, Dept Urol, Taoyuan, Taiwan

来源：

REDOX BIOLOGY | 2017年 / 13卷

关键词：

Specificity protein 1; Superoxide dismutase 2; Reactive oxygen species; Temozolomide; O-6-methylguanine-DNA methyltransferase; TRANSCRIPTION FACTOR SP1; OXIDATIVE STRESS; 179; PATHWAY; STEM-CELLS; GLIOMA; EXPRESSION; GENE; MECHANISMS; CONTRIBUTES; INDUCTION;

D O I：

10.1016/j.redox.2017.08.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 O-6-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.

引用

页码：655 / 664

页数：10

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