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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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DN200434, an orally available inverse agonist of estrogen-related receptor γ, induces ferroptosis in sorafenib-resistant hepatocellular carcinoma

  • Dong-Ho, Kim (Department of Biomedical Science, Kyungpook National University) ;
  • Mi-Jin, Kim (Research Institute of Aging and Metabolism, Kyungpook National University) ;
  • Na-Young, Kim (Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital) ;
  • Seunghyeong, Lee (Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital) ;
  • Jun-Kyu, Byun (BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University) ;
  • Jae Won, Yun (Veterans Medical Research Institute, Veterans Health Service Medical Center) ;
  • Jaebon, Lee (Sungkyunkwan University School of Medicine) ;
  • Jonghwa, Jin (Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital) ;
  • Jina, Kim (New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Jungwook, Chin (New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Sung Jin, Cho (Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology) ;
  • In-Kyu, Lee (Department of Biomedical Science, Kyungpook National University) ;
  • Yeon-Kyung, Choi (Research Institute of Aging and Metabolism, Kyungpook National University) ;
  • Keun-Gyu, Park (Department of Biomedical Science, Kyungpook National University)
  • Received : 2022.05.23
  • Accepted : 2022.08.01
  • Published : 2022.11.30
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Abstract

Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib.

Keywords

Acknowledgement

This work was supported by National Research Foundation of Korea (NRF) grants NRF-2021R1A2C3005603, NRF-2017M3A9G7073086, 2022R1A2C1008591, and NRF-2020R1A5A2017323, funded by the Ministry of Science and the ICT; and by grant HI16C1501 from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare.

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