Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
Anticancer Res. 2014 Jun;34(6):2957-66.
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.
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.
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.
Hyperoxia enhanced GBM cell sensitivity to temozolomide, likely through UPR, highlighting an important treatment modality targeting chemosensitive and -resistant GBM.
脑胶质瘤多形性（GBM）是一种高度恶性的脑肿瘤，肿瘤内缺氧与化疗耐药有关。替莫唑胺诱导的内质网应激的适应性反应是复发性 GBM 的主要障碍。我们研究了高氧是否通过消除缺氧诱导的未折叠蛋白反应（UPR）相关保护机制使替莫唑胺耐药的 GBM 细胞对替莫唑胺重新敏感。
我们使用 Western blot 检测了在不同氧浓度下用/不用替莫唑胺处理的替莫唑胺敏感和耐药的人 GBM 细胞（D54 和 U87）中关键 UPR 调节剂的变化，并在常氧和高氧条件下在 GBM 细胞（U87 和 U251）中转染关键伴侣蛋白 P4HB 后观察细胞的细胞毒性获益。
高氧单独或与替莫唑胺协同作用激活了敏感和耐药的 D54 和 U87 细胞系中的 UPR。高氧还通过 UPR 降低了 U87 和 U251 细胞中 P4HB 过表达的生存获益。
高氧增强了 GBM 细胞对替莫唑胺的敏感性，可能通过 UPR，突出了一种针对化疗敏感和耐药 GBM 的重要治疗方式。
