Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase
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 u...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-10-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231717305888 |
| _version_ | 1819147068770353152 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kwang-Yu Chang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T13:23:57Z |
| format | Article |
| id | doaj.art-2cfb7d3e1f924bd3bbb0af1a34f9768a |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-22T13:23:57Z |
| publishDate | 2017-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-2cfb7d3e1f924bd3bbb0af1a34f9768a2022-12-21T18:24:23ZengElsevierRedox Biology2213-23172017-10-0113C65566410.1016/j.redox.2017.08.005Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferaseKwang-Yu Chang0Tsung-I. Hsu1Che-Chia Hsu2Shan-Yin Tsai3Jr-Jiun Liu4Shao-Wen Chou5Ming-Sheng Liu6Jing-Ping Liou7Chiung-Yuan Ko8Kai-Yun Chen9Jan-Jong Hung10Wen-Chang Chang11Cheng-Keng Chuang12Tzu-Jen Kao13Jian-Ying Chuang14National Institute of Cancer Research, National Health Research Institutes, TaiwanCenter for Neurotrauma and Neuroregeneration, Taipei Medical University, TaiwanGraduate Institute of Medical Science, Taipei Medical University, TaiwanAn Nan Hospital, China Medical University, TaiwanNational Institute of Cancer Research, National Health Research Institutes, TaiwanNational Institute of Cancer Research, National Health Research Institutes, TaiwanNational Institute of Cancer Research, National Health Research Institutes, TaiwanSchool of Pharmacy, Taipei Medical University, TaiwanThe Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, TaiwanThe Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, TaiwanInstitute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, TaiwanGraduate Institute of Medical Science, Taipei Medical University, TaiwanDepartment of Medicine, Chang Gung University, TaiwanCenter for Neurotrauma and Neuroregeneration, Taipei Medical University, TaiwanCenter for Neurotrauma and Neuroregeneration, Taipei Medical University, TaiwanAcquisition 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.http://www.sciencedirect.com/science/article/pii/S2213231717305888Specificity protein 1Superoxide dismutase 2Reactive oxygen speciesTemozolomideO6-methylguanine-DNA methyltransferase |
| spellingShingle | 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 Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase Redox Biology Specificity protein 1 Superoxide dismutase 2 Reactive oxygen species Temozolomide O6-methylguanine-DNA methyltransferase |
| title | Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase |
| title_full | Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase |
| title_fullStr | Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase |
| title_full_unstemmed | Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase |
| title_short | Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase |
| title_sort | specificity protein 1 modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma which is independent of o6 methylguanine dna methyltransferase |
| topic | Specificity protein 1 Superoxide dismutase 2 Reactive oxygen species Temozolomide O6-methylguanine-DNA methyltransferase |
| url | http://www.sciencedirect.com/science/article/pii/S2213231717305888 |
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