2. Academic Validation
  3. 17β-estradiol induces temozolomide resistance through NRF2-mediated redox homeostasis in glioblastoma

17β-estradiol induces temozolomide resistance through NRF2-mediated redox homeostasis in glioblastoma

  • Free Radic Biol Med. 2021 Aug 20;172:430-440. doi: 10.1016/j.freeradbiomed.2021.06.028.
Hong-Yi Lin 1,  Kuo-Hsing Liao 2,  Chiung-Yuan Ko 3,  Guan-Yuan Chen 4,  Sung-Po Hsu 5,  Chia-Yang Hung 6,  Tsung-I Hsu 7
Affiliations

Affiliations

  • 1 The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institute, Taipei, Taiwan.
  • 2 Department of Neurosurgery, Wan Fang Hospital, Taipei Medical University, Taiwan; Division of Critical Medicine, Department of Emergency and Critical Medicine, Wan Fang Hospital, Taipei Medical University, Taiwan; Department of Neurotraumatology and Intensive Care, Taipei Neuroscience Institute, Taipei Medical University, Taiwan; Division of Neurosurgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taiwan.
  • 3 The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institute, Taipei, Taiwan; Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei, Taiwan.
  • 4 Graduate Institute of Forensic Medicine, National Taiwan University, Taipei, Taiwan.
  • 5 Department of Physiology, School of Medicine, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 6 Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 7 The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institute, Taipei, Taiwan; Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: [email protected].
PMID: 34186205 DOI: 10.1016/j.freeradbiomed.2021.06.028
Abstract

Glioblastoma multiforme (GBM) is the most fatal Cancer among brain tumors, and the standard treatment of GBM patients is surgical tumor resection followed by radiotherapy and temozolomide (TMZ) chemotherapy. However, tumors always recur due to the developing drug resistance. It has been shown that neurosteroids, including dehydroepiandrosterone and 17β-estradiol, are synthesized in TMZ-resistant GBM tumors. Therefore, we sought to explore the possible role of 17β-estradiol in the development of drug resistance in GBM. Bioinformatics analysis revealed that Aromatase/Cytochrome P450 19A1 expression was gradually increased in the development from normal, astrocytoma to GBM. The level of 17β-estradiol was significantly increased in TMZ-resistant cells characterized by ultra performance liquid chromatography-tandem mass spectrometry. Furthermore, 17β-estradiol attenuated TMZ-induced cell death and reduced Reactive Oxygen Species production by mitochondria. In addition, 17β-estradiol attenuated oxidative stress by increasing the expression of superoxide dismutase 1/2, catalase, and nuclear factor erythroid 2-related factor (NRF) 2. We found that NRF2 expression was essential for the induction of drug resistance by 17β-estradiol through the reduction of oxidative stress in GBM.

Keywords

17β-estradiol; Aromatase; Drug resistance; Glioblastoma; NRF2; Neurosteroid; Temozolomide.

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