Weatherbee Jessica L, Kraus Jean-Louis, Ross Alonzo H
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Developmental Biology Institute of Marseille-Luminy (IBDML), Aix-Marseille University (AMU) and CNRS, UMR 7288, IBDML, Case 907, Marseille, France.
Oncotarget. 2016 Jul 12;7(28):43820-43834. doi: 10.18632/oncotarget.9907.
Glioblastoma multiforme (GBM) is a deadly grade IV brain tumor. Radiation in combination with temozolomide (TMZ), the current chemotherapeutic for GBMs, only provides 12-14 months survival post diagnosis. Because GBMs are dependent on both activation of the DNA damage pathway and the endoplasmic reticulum (ER) stress response, we asked if a novel ER stress inducing agent, JLK1486, increases the efficacy of TMZ.We found that the combination of TMZ+JLK1486 resulted in decreased proliferation in a panel of adherent GBM cells lines and reduced secondary sphere formation in non-adherent and primary lines. Decreased proliferation correlated with increased cell death due to apoptosis. We found prolonged ER stress in TMZ+JLK1486 treated cells that resulted in sustained activation of the unfolded protein response (UPR) through increased levels of BiP, ATF4, and CHOP. In addition, TMZ+JLK1486 treatment caused decreased RAD51 levels, impairing DNA damage repair. Furthermore, we found delayed time to tumor doubling in TMZ+JLK1486 treated mice.Our data shows that the addition of JLK1486 to TMZ increases the efficaciousness of the treatment by decreasing proliferation and inducing cell death. We propose increased cell death is due to two factors. One, prolonged ER stress driving the expression of the pro-apoptotic transcription factor CHOP, and, second, unresolved DNA double strand breaks, due to decreased RAD51 levels. The combination of TMZ+JLK1486 is a potential novel therapeutic combination and suggests an inverse relationship between unresolved ER stress and the DNA damage response pathway.
多形性胶质母细胞瘤（GBM）是一种致命的IV级脑肿瘤。放疗联合替莫唑胺（TMZ），即目前用于治疗GBM的化疗药物，仅能使患者在确诊后存活12 - 14个月。由于GBM既依赖于DNA损伤途径的激活，也依赖于内质网（ER）应激反应，我们探究了一种新型的ER应激诱导剂JLK1486是否能提高TMZ的疗效。我们发现，TMZ与JLK1486联合使用可导致一组贴壁GBM细胞系的增殖减少，并减少非贴壁和原代细胞系中的二次球体形成。增殖减少与凋亡导致的细胞死亡增加相关。我们发现，经TMZ + JLK1486处理的细胞中ER应激延长，这通过BiP、ATF4和CHOP水平的升高导致未折叠蛋白反应（UPR）持续激活。此外，TMZ + JLK1486处理导致RAD51水平降低，损害DNA损伤修复。此外，我们发现经TMZ + JLK1486处理的小鼠肿瘤倍增时间延迟。我们的数据表明，在TMZ中添加JLK1486可通过减少增殖和诱导细胞死亡来提高治疗效果。我们认为细胞死亡增加是由于两个因素。一是延长的ER应激驱动促凋亡转录因子CHOP的表达，二是由于RAD51水平降低导致未解决的DNA双链断裂。TMZ + JLK1486的联合使用是一种潜在的新型治疗组合，并表明未解决的ER应激与DNA损伤反应途径之间存在反向关系。
