- 作者: 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
- 作者服務機構: 1.Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA 2.Department of Neurosurgery, Keelung Chang Gung Memorial Hospital, Keelung, 204, Taiwan 3.Department of Neurosurgery, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan 4.Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, Taipei, 110, Taiwan 5.Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan 6.Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan, 110 7.Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan 8.National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan 9.Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan 10.Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 110, Taiwan 11.School of Medicine, Chang Gung University, Taoyuan City, 33302, Taiwan 12.TMU Research Center of Cancer Translational Medicine, Taipei, 110, Taiwan 13.TMU Research Center of Neuroscience, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan
- 中文摘要:
- 英文摘要:
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. - 中文關鍵字:
- 英文關鍵字: TMZ-resistant GBM, Sp1, PGE2, Mitochondria, Fatty acid β-oxidation