Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation
Abstract Background Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. Methods RNA-Seq and mass spectrometry were used to analyze gene expres...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-03-01
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| Series: | Journal of Biomedical Science |
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| Online Access: | https://doi.org/10.1186/s12929-022-00804-3 |
| _version_ | 1811332135480459264 |
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| author | Yu-Ting Tsai Wei-Lun Lo Pin-Yuan Chen Chiung-Yuan Ko Jian-Ying Chuang Tzu-Jen Kao Wen-Bing Yang Kwang-Yu Chang Chia-Yang Hung Ushio Kikkawa Wen-Chang Chang Tsung-I. Hsu |
| author_facet | Yu-Ting Tsai Wei-Lun Lo Pin-Yuan Chen Chiung-Yuan Ko Jian-Ying Chuang Tzu-Jen Kao Wen-Bing Yang Kwang-Yu Chang Chia-Yang Hung Ushio Kikkawa Wen-Chang Chang Tsung-I. Hsu |
| author_sort | Yu-Ting Tsai |
| collection | DOAJ |
| description | Abstract Background Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. Methods RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo. Results Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid β-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ. Conclusion Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM. |
| first_indexed | 2024-04-13T16:32:13Z |
| format | Article |
| id | doaj.art-41e5eb2931d64c3ea1398dfe091319be |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-04-13T16:32:13Z |
| publishDate | 2022-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj.art-41e5eb2931d64c3ea1398dfe091319be2022-12-22T02:39:32ZengBMCJournal of Biomedical Science1423-01272022-03-0129111710.1186/s12929-022-00804-3Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidationYu-Ting Tsai0Wei-Lun Lo1Pin-Yuan Chen2Chiung-Yuan Ko3Jian-Ying Chuang4Tzu-Jen Kao5Wen-Bing Yang6Kwang-Yu Chang7Chia-Yang Hung8Ushio Kikkawa9Wen-Chang Chang10Tsung-I. Hsu11Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityDepartment of Surgery, School of Medicine, College of Medicine, Taipei Medical UniversitySchool of Medicine, Chang Gung UniversityTMU Research Center of Neuroscience, Taipei Medical UniversityTMU Research Center of Neuroscience, Taipei Medical UniversityTMU Research Center of Neuroscience, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityNational Institute of Cancer Research, National Health Research InstitutesDepartment of Immuno-Oncology, Beckman Research Institute, City of HopeGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityTMU Research Center of Neuroscience, Taipei Medical UniversityAbstract Background Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. Methods RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo. Results Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid β-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ. Conclusion Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM.https://doi.org/10.1186/s12929-022-00804-3TMZ-resistant GBMSp1PGE2MitochondriaFatty acid β-oxidation |
| spellingShingle | Yu-Ting Tsai Wei-Lun Lo Pin-Yuan Chen Chiung-Yuan Ko Jian-Ying Chuang Tzu-Jen Kao Wen-Bing Yang Kwang-Yu Chang Chia-Yang Hung Ushio Kikkawa Wen-Chang Chang Tsung-I. Hsu Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation Journal of Biomedical Science TMZ-resistant GBM Sp1 PGE2 Mitochondria Fatty acid β-oxidation |
| title | Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation |
| title_full | Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation |
| title_fullStr | Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation |
| title_full_unstemmed | Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation |
| title_short | Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation |
| title_sort | reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation |
| topic | TMZ-resistant GBM Sp1 PGE2 Mitochondria Fatty acid β-oxidation |
| url | https://doi.org/10.1186/s12929-022-00804-3 |
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