Regulation of Integrated Stress Response Sensitizes U87MG Glioblastoma Cells to Temozolomide Through the Mitochondrial Apoptosis Pathway.

Glioblastomas are the most frequently diagnosed and worst primary malignancy of the central nervous system, with very poor prognosis. The first-line antiglioma drug temozolomide shows decreasing therapeutic efficacy as treatment progresses. As the integrated stress response (ISR) may be a resistance factor and severe stress might transform the protective effect of the ISR into a damage effect, pharmacological regulation of ISR may be an effective way to sensitize glioma to temozolomide. The aim of the present study was to investigate the mechanisms of the ISR in regulating the therapeutic effect of temozolomide in the human glioblastoma multiforme cell line U87MG. Cultured U87MG cells were treated with temozolomide and PCR array was used to screen key factors in the response to treatment. Cells were co-treated with temozolomide and the eIF2α phosphatase inhibitor salubrinal, and cell apoptosis was measured. Combination treatment with temozolomide and salubrinal had a synergistic effect on cell viability. Salubrinal could upregulate the expression of ATF4, a key factor in the ISR, and enhance temozolomide-induced apoptosis. ATF4 transcriptionally regulated expression of the BH3-ONLY protein NOXA, thus inducing mitochondrial apoptosis. These findings suggest that ISR and ATF4 are involved in the death crosstalk between the endoplasmic reticulum and mitochondria and might be a potential target to enhance the therapeutic effect of temozolomide in patients with glioblastoma multiforme. Anat Rec, 2018.