Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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AXL is required for hypoxia-mediated hypoxia-inducible factor-1 alpha function in glioblastoma

  • Thuy‑Trang T. Vo (Department of Pharmacology, College of Medicine, Chungnam National University) ;
  • Quangdon Tran (Department of Pharmacology, College of Medicine, Chungnam National University) ;
  • Youngeun Hong (Department of Pharmacology, College of Medicine, Chungnam National University) ;
  • Hyunji Lee (Department of Pharmacology, College of Medicine, Chungnam National University) ;
  • Hyeonjeong Cho (Department of Pharmacology, College of Medicine, Chungnam National University) ;
  • Minhee Kim (Department of Pharmacology, College of Medicine, Chungnam National University) ;
  • Sungjin Park (Department of Pharmacology, College of Medicine, Chungnam National University) ;
  • Chaeyeong Kim (Department of Pharmacology, College of Medicine, Chungnam National University) ;
  • Choinyam Bayarmunkh (Department of Graduate Education, Graduate School, Mongolian National University of Medical Sciences) ;
  • Damdindorj Boldbaatar (Department of Graduate Education, Graduate School, Mongolian National University of Medical Sciences) ;
  • So Hee Kwon (College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University) ;
  • Jisoo Park (Department of Pharmacology, College of Medicine, Chungnam National University) ;
  • Seon‑Hwan Kim (Department of Neurosurgery, Institute for Cancer Research, College of Medicine, Chungnam National University) ;
  • Jongsun Park (Department of Pharmacology, College of Medicine, Chungnam National University)
  • Received : 2023.01.16
  • Accepted : 2023.05.24
  • Published : 2023.10.15
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Abstract

Glioblastoma (GBM) is the most aggressive type of central nervous system tumor. Molecular targeting may be important when developing efficient GBM treatment strategies. Sequencing of GBMs revealed that the receptor tyrosine kinase (RTK)/RAS/phosphatidylinositol-3-kinase pathway was altered in 88% of samples. Interestingly, AXL, a member of RTK, was proposed as a promising target in glioma therapy. However, the molecular mechanism of AXL modulation of GBM genesis and proliferation is still unclear. In this study, we investigated the expression and localization of hypoxia-inducible factor-1 alpha (HIF-1α) by AXL in GBM. Both AXL mRNA and protein are overexpressed in GBM. Short-interfering RNA knockdown of AXL in U251-MG cells reduced viability and migration. However, serum withdrawal reduced AXL expression, abolishing the effect on viability. AXL is also involved in hypoxia regulation. In hypoxic conditions, the reduction of AXL decreased the level and nuclear localization of HIF-1α. The co-expression of HIF-1α and AXL was found in human GBM samples but not normal tissue. This finding suggests a mechanism for GBM proliferation and indicates that targeting AXL may be a potential GBM therapeutic.

Keywords

Acknowledgement

This work was financially supported by a research fund from Chungnam National University (grant to S.H. Kim) and by the Brain Korea 21 PLUS Project for Medical Science, Chungnam National University School of Medicine. This study was also supported by a research fund from Mongolian Foundation for Science and Technology (ShU/x/So-2017/06)

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