The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma.
The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma.
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DOI：
10.18632/oncotarget.6712
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发表时间：
2016-01-12
期刊：
影响因子：
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通讯作者：
Hallahan DE
中科院分区：
文献类型：
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作者：
Dadey DY;Kapoor V;Khudanyan A;Urano F;Kim AH;Thotala D;Hallahan DE
治疗耐药性是胶质母细胞瘤患者预后改善的主要障碍。内质网应激反应（ERSR）已被确定为胶质母细胞瘤化疗耐药的一个因素；然而，ERSR对抗辐射的贡献尚未得到表征。在这项研究中，我们发现辐射可以诱导内质网应激和与ERSR相关的下游信号传导。内质网应激的诱导似乎与辐照后ROS平衡的变化有关。此外，我们观察到辐照胶质母细胞瘤中ERSR下游基因的全局诱导。敲低ERSR调节因子ATF6足以增强辐射诱导的细胞死亡。此外，我们发现ATF6的激活有助于辐射诱导的葡萄糖调节蛋白78 （GRP78）和NOTCH1的上调。我们的研究结果表明ATF6是一个潜在的治疗靶点，可以提高放射治疗的疗效。
Therapeutic resistance is a major barrier to improvement of outcomes for patients with glioblastoma. The endoplasmic reticulum stress response (ERSR) has been identified as a contributor to chemoresistance in glioblastoma; however the contributions of the ERSR to radioresistance have not been characterized. In this study we found that radiation can induce ER stress and downstream signaling associated with the ERSR. Induction of ER stress appears to be linked to changes in ROS balance secondary to irradiation. Furthermore, we observed global induction of genes downstream of the ERSR in irradiated glioblastoma. Knockdown of ATF6, a regulator of the ERSR, was sufficient to enhance radiation induced cell death. Also, we found that activation of ATF6 contributes to the radiation-induced upregulation of glucose regulated protein 78 (GRP78) and NOTCH1. Our results reveal ATF6 as a potential therapeutic target to enhance the efficacy of radiation therapy.