Department of Neurosurgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China.
Department of Neurosurgery, The First Affiliated Hospital of Jilin University, Changchun, Jilin, China.
Anat Rec (Hoboken). 2018 Aug;301(8):1390-1397. doi: 10.1002/ar.23839. Epub 2018 May 13.
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. © 2018 Wiley Periodicals, Inc.
胶质母细胞瘤是中枢神经系统中最常见和最严重的原发性恶性肿瘤，预后极差。一线抗胶质瘤药物替莫唑胺随着治疗的进展，其治疗效果逐渐降低。由于整合应激反应（ISR）可能是一种耐药因素，严重应激可能会将 ISR 的保护作用转化为损伤作用，因此，ISR 的药理学调节可能是一种使胶质母细胞瘤对替莫唑胺敏感的有效方法。本研究旨在探讨 ISR 在调节替莫唑胺对人多形性胶质母细胞瘤 U87MG 细胞系治疗效果中的作用机制。用替莫唑胺处理培养的 U87MG 细胞，并使用 PCR 阵列筛选对治疗反应的关键因素。将细胞与替莫唑胺和 eIF2α 磷酸酶抑制剂 salubrinal 共同处理，并测量细胞凋亡。替莫唑胺和 salubrinal 的联合治疗对细胞活力具有协同作用。Salubrinal 可上调 ISR 中的关键因子 ATF4 的表达，并增强替莫唑胺诱导的细胞凋亡。ATF4 转录调控 BH3-ONLY 蛋白 NOXA 的表达，从而诱导线粒体凋亡。这些发现表明 ISR 和 ATF4 参与内质网和线粒体之间的死亡串扰，可能是增强替莫唑胺治疗多形性胶质母细胞瘤患者疗效的潜在靶点。解剖学记录，2018 年。© 2018 年 Wiley Periodicals, Inc.
