Hyperoxia resensitizes chemoresistant glioblastoma cells to temozolomide through unfolded protein response.

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.