title: Hyperoxia resensitizes chemoresistant glioblastoma cells to temozolomide through unfolded protein response.
abstract: BACKGROUND
  Intratumoural hypoxia is associated with chemoresistance in glioblastoma multiforme (GBM), a highly malignant brain tumour. Adaptive response to endoplasmic reticulum stress induced by temozolomide is a major obstacle in recurrent GBM. We investigated whether hyperoxia resensitizes temozolomide-resistant GBM cells to temozolomide by abrogating the hypoxia-induced, unfolded protein response (UPR)-related protective mechanisms.
  
  
  METHODS
  We examined changes to key UPR modulators in temozolomide-sensitive and -resistant human GBM cells (D54 and U87) treated with/without temozolomide at different oxygen concentrations using western blotting, and cytotoxic benefits of overexpressing key chaperone, P4HB, in GBM cells (U87 and U251) under normoxia and hyperoxia.
  
  
  RESULTS
  Hyperoxia, alone or synergistically with temozolomide, activated the UPR in sensitive and resistant D54 and U87 cell lines. Hyperoxia also reduced survival benefit of U87 and U251 cells with P4HB overexpression through the UPR.
  
  
  CONCLUSIONS
  Hyperoxia enhanced GBM cell sensitivity to temozolomide, likely through UPR, highlighting an important treatment modality targeting chemosensitive and -resistant GBM.
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Derek
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Stella
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Amy S W
authors.initials: AS
authors.lastname: Ho
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Karrie M Y
authors.initials: KM
authors.lastname: Kiang
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Xiao Qin
authors.initials: XQ
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
authors.forename: Fei Fan
authors.initials: FF
authors.lastname: Xu
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong gilberto@hku.hk.
authors.forename: Gilberto K K
authors.initials: GK
authors.lastname: Leung
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D018496:Hyperoxia; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D011393:Procollagen-Proline Dioxygenase; C526497:P4HB protein, human; D019704:Protein Disulfide-Isomerases; D000077204:Temozolomide
keywords: ER stress response; Glioblastoma; P4HB; chemoresistance; hyperoxia; temozolomide